Methods for treating a headache condition using anti-human PAC1 antibodies or antigen-binding fragments thereof

ABSTRACT

The present invention relates to neutralizing antibodies of the human pituitary adenylate cyclase activating polypeptide type I receptor (PAC1) and pharmaceutical compositions comprising such antibodies. Methods of treating or preventing headache conditions, such as migraine and cluster headache, using the neutralizing antibodies are also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.16/246,326, now U.S. Pat. No. 10,738,110, filed Jan. 11, 2019, whichclaims the benefit of U.S. Provisional Application No. 62/617,157, filedJan. 12, 2018, both of which are hereby incorporated by reference intheir entireties.

DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

The present application contains a Sequence Listing, which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. The computer readable format copy of theSequence Listing, which was created on Jul. 1, 2020, is namedA-2189-US-DIV_SeqList_ST25 and is 490 kilobytes in size.

FIELD OF THE INVENTION

The present invention relates to the field of biopharmaceuticals. Inparticular, the invention relates to antibodies that specifically bindto human pituitary adenylate cyclase-activating polypeptide type Ireceptor (PAC1) and potently inhibit its biological activity. Theinvention also relates to pharmaceutical compositions comprising theantibodies as well as methods of producing and using such antibodies.

BACKGROUND OF THE INVENTION

Migraines are episodic headaches that can involve significant pain, areoften accompanied by nausea, vomiting, and extreme sensitivity to light(photophobia) and sound (phonophobia), and are sometimes preceded bysensory warning symptoms or signs (auras). Migraine is a highlyprevalent disease worldwide with approximately 12% of the Europeanpopulation, and 18% of women, 6% of men in the United States sufferingfrom migraine attacks (Lipton et al, Neurology, Vol. 68:343-349, 2007;Lipton et al., Headache, Vol. 41:646-657, 2001). A study to assess theprevalence of migraine in the United States reported that nearly halfthe migraine patient population had three or more migraines per month(Lipton et al, Neurology, Vol. 68:343-349, 2007). Additionally,migraines are associated with a number of psychiatric and medicalcomorbidities such as depression and vascular disorders (Buse et al., J.Neurol. Neurosurg. Psychiatry, Vol. 81:428-432, 2010; Bigal et al.,Neurology, Vol. 72:1864-1871, 2009). Most of the current migrainetherapies are either not well tolerated or ineffective (Loder et al.,Headache, Vol. 52:930-945, 2012; Lipton et al, 2001); thus, migraineremains an unmet medical need.

A major component of migraine pathogenesis involves the activation ofthe trigeminovascular system. The release of trigeminal andparasympathetic neurotransmitters from perivascular nerve fibers(Sánchez-del-Rio and Reuter, Curr. Opin. Neurol., Vol. 17(3):289-93,2004) results in vasodilation of the cranial blood vessels and has beensuggested to be associated with the onset of migraine headaches(Edvinsson, Cephalagia, Vol. 33(13): 1070-1072, 2013; Goadsby et al.,New Engl J Med., Vol. 346(4):257-270, 2002).

Pituitary adenylate cyclase-activating polypeptides (PACAP) are 38-aminoacid (PACAP38), or 27-amino acid (PACAP27) peptides that were firstisolated from an ovine hypothalamic extract on the basis of theirability to stimulate cyclic AMP (cAMP) formation in anterior pituitarycells (Miyata et al., Biochem Biophys Res Commun., Vol. 164:567-574,1989; Miyata et al., Biochem Biophys Res Commun., Vol. 170:643-648,1990). PACAP belongs to the VIP/secretin/glucagon superfamily. Thesequence of PACAP27 corresponds to the 27 N-terminal amino acids ofPACAP38 and shares 68% identity with vasoactive intestinal polypeptide(VIP) (Pantaloni et al., J. Biol. Chem., Vol. 271: 22146-22151, 1996;Pisegna and Wank, Proc. Natl. Acad. Sci. USA, Vol. 90: 6345-49, 1993;Campbell and Scanes, Growth Regul., Vol. 2:175-191, 1992). The majorform of PACAP peptide in the human body is PACAP38, and the pharmacologyof PACAP38 has not been shown to be different from the pharmacology ofPACAP27. Three PACAP receptors have been reported: one receptor thatbinds PACAP with high affinity and has a much lower affinity for VIP(PAC1 receptor), and two receptors that recognize PACAP and VIP equallywell (VPAC1 and VPAC2 receptors) (Vaudry et al., Pharmacol Rev., Vol.61:283-357, 2009).

Human experimental migraine models using PACAP as a challenge agent toinduce migraine-like headaches support the approach for antagonism ofthe PACAP/PAC1 signaling pathway as a treatment for migraineprophylaxis. PACAP38 is elevated in plasma during spontaneous migraineattacks in migraine patients, and these elevated PACAP38 levels can benormalized with sumatriptan, an acute migraine therapy (Tuka et al.,Cephalalgia, Vol. 33: 1085-1095, 2013; Zagami et al., Ann. Clin. Transl.Neurol., Vol. 1: 1036-1040, 2014). Infusion of PACAP38 causes headachesin healthy subjects and migraine-like headaches in migraine patients(Schytz et al., Brain, Vol. 132:16-25, 2009; Amin et al., Brain, Vol.137: 779-794, 2014; Guo et al., Cephalalgia, Vol. 37:125-135, 2017).However, in the same model, VIP does not cause migraine-like headachesin migraine patients (Rahmann et al., Cephalalgia, Vol. 28:226-236,2008). The lack of migraine-like headache induction from VIP infusionsuggests that PACAP38 peptide's effects are mediated through the PAC1receptor, rather than VPAC1 or VPAC2 receptors, because VIP has a muchhigher affinity at the latter two receptors. This notion is furthersupported by animal studies in which PAC1 receptor antagonists inhibitnociceptive neuronal activity in the trigeminocervical complex in an invivo model of migraine (Akerman et al., Sci. Transl. Med., Vol. 7:308ra157, 2015; Hoffmann et al., Cephalalgia, Vol. 37 (1S): 3, AbstractOC-BA-004, 2017). Taken together, these data suggest thatpharmacological agents that inhibit PACAP-activation of the PAC1receptor have the potential to treat migraine.

SUMMARY OF THE INVENTION

The present invention is based, in part, on the design and generation ofhigh affinity antibodies that specifically bind to and potently inhibithuman PAC1. The antibodies of the invention have enhanced inhibitorypotency against human PAC1 as compared to previously described anti-PAC1antibodies, with IC50 values in the picomolar range. The isolatedantibodies and antigen-binding fragments thereof can be used to inhibit,interfere with, or modulate the biological activity of human PAC1,including inhibiting or reducing PACAP-induced activation of PAC1,inhibiting or reducing vasodilation, and ameliorating or treatingsymptoms of migraine and other vascular headaches.

In some embodiments, the isolated antibodies and antigen-bindingfragments thereof specifically bind to human PAC1 at an epitope thatcomprises one or more amino acids selected from Asp59, Asn60, Ile61,Arg116, Asn117, Thr119, Glu120, Asp121, Gly122, Trp123, Ser124, Glu125,Pro126, Phe127, Pro128, His129, Tyr130, Phe131, Asp132, and Gly135 ofSEQ ID NO: 1. In certain embodiments, the epitope comprises at leastamino acids Asn60, Ile61, Glu120, and Asp121 of human PAC1. In these andother embodiments, the antibodies and antigen-binding fragments of theinvention comprise specific amino acids at particular positions withinthe light chain and heavy chain variable regions that interact withthese epitope residues. For instance, in one embodiment, the antibodiesor antigen-binding fragments comprise a light chain variable region inwhich the amino acid at position 29 according to AHo numbering is abasic amino acid (e.g. arginine or lysine) that interacts with aminoacids Glu120 or Asp121 of human PAC1. In another embodiment, theantibodies or antigen-binding fragments comprise a heavy chain variableregion in which the amino acid at position 61 according to AHo numberingis a hydrophobic, basic, or neutral hydrophilic amino acid (e.g.isoleucine, valine, leucine, glutamine, asparagine, arginine, or lysine)that interacts with amino acids Asn60 or Ile61 of human PAC1. In yetanother embodiment, the antibodies or antigen-binding fragments comprisea heavy chain variable region in which the amino acid at position 66according to AHo numbering is a basic or neutral hydrophilic amino acid(e.g. glutamine, asparagine, arginine, or lysine) that interacts withamino acids Asn60 or Ile61 of human PAC1.

The anti-PAC1 antibodies and antigen-binding fragments of the inventioncan inhibit ligand-induced activation of the PAC1 receptor. Forinstance, in some embodiments, the anti-PAC1 antibodies andantigen-binding fragments inhibit PACAP-induced activation of human PAC1with an IC50 less than 500 pM as measured by a cell-based cAMP assay. Inother embodiments, the anti-PAC1 antibodies and antigen-bindingfragments inhibit PACAP-induced activation of human PAC1 with an IC50less than 300 pM as measured by a cell-based cAMP assay. In certainembodiments, the anti-PAC1 antibodies and antigen-binding fragmentsinhibit PACAP-induced activation of the human PAC1 receptor with an IC50between about 50 pM and about 500 pM as measured by a cell-based cAMPassay.

In some embodiments, the anti-PAC1 antibodies and antigen bindingfragments of the invention cross-react with PAC1 receptors from otherspecies. In one embodiment, the anti-PAC1 antibodies or antigen-bindingfragments specifically bind to and inhibit PACAP-induced activation ofthe cynomolgus monkey PAC1 receptor. In such an embodiment, theanti-PAC1 antibodies or antigen-binding fragments may inhibitPACAP-induced activation of the cynomolgus monkey PAC1 receptor with anIC50 between about 0.1 nM and about 1 nM or between about 50 pM andabout 500 pM as measured by a cell-based cAMP assay. In anotherembodiment, the anti-PAC1 antibodies or antigen-binding fragmentsspecifically bind to and inhibit PACAP-induced activation of the ratPAC1 receptor. The anti-PAC1 antibodies or antigen-binding fragments mayinhibit PACAP-induced activation of the rat PAC1 receptor with an IC50less than 10 nM, for example with an IC50 between about 0.1 nM and about10 nM or between about 100 pM and about 2 nM as measured by a cell-basedcAMP assay.

In certain embodiments, the anti-PAC1 antibodies or antigen-bindingfragments of the invention comprise a light chain variable regioncomprising complementarity determining regions CDRL1, CDRL2, and CDRL3and a heavy chain variable region comprising complementarity determiningregions CDRH1, CDRH2, and CDRH3. The light chain and heavy chainvariable regions or CDRs may be from any of the anti-PAC1 antibodiesdescribed herein. For instance, in some embodiments, the anti-PAC1antibodies or antigen-binding fragments comprise a CDRL1 comprising asequence selected from SEQ ID NOs: 5-16; a CDRL2 comprising the sequenceof SEQ ID NO: 26; a CDRL3 comprising a sequence selected from SEQ IDNOs: 36-38; a CDRH1 comprising a sequence selected from SEQ ID NOs:88-96; a CDRH2 comprising a sequence selected from SEQ ID NOs: 106-166;and a CDRH3 comprising a sequence selected from SEQ ID NOs: 171-177. Inother embodiments, the anti-PAC1 antibodies or antigen-binding fragmentscomprise a CDRL1 comprising a sequence selected from SEQ ID NOs: 17-25;a CDRL2 comprising a sequence selected from SEQ ID NOs: 27-35; a CDRL3comprising a sequence selected from SEQ ID NOs: 39-51; a CDRH1comprising a sequence selected from SEQ ID NOs: 97-105; a CDRH2comprising a sequence selected from SEQ ID NOs: 167-170; and a CDRH3comprising a sequence selected from SEQ ID NOs: 178-190.

In some embodiments, the anti-PAC1 antibodies or antigen-bindingfragments of the invention comprise a light chain variable region thatcomprises a sequence that is at least 90% identical or at least 95%identical to a sequence selected from SEQ ID NOs: 54-66 and SEQ ID NOs:68-87. In these and other embodiments, the anti-PAC1 antibodies orantigen-binding fragments of the invention comprise a heavy chainvariable region that comprises a sequence that is at least 90% identicalor at least 95% identical to a sequence selected from SEQ ID NOs:191-312. In one embodiment, the anti-PAC1 antibodies or antigen-bindingfragments comprise a light chain variable region comprising a sequenceselected from SEQ ID NOs: 54-66 and a heavy chain variable regioncomprising a sequence selected from SEQ ID NOs: 191-295. In anotherembodiment, the anti-PAC1 antibodies or antigen-binding fragmentscomprise a light chain variable region comprising a sequence selectedfrom SEQ ID NOs: 68-87 and a heavy chain variable region comprising asequence selected from SEQ ID NOs: 296-312.

In any of the embodiments described herein, including the embodimentsdescribed above, the anti-PAC1 antibody or antigen-binding fragment ofthe invention is a monoclonal antibody or antigen-binding fragmentthereof. In some embodiments, the monoclonal antibody or antigen-bindingfragment thereof is a chimeric antibody or antigen-binding fragmentthereof. In other embodiments, the monoclonal antibody orantigen-binding fragment thereof is a humanized antibody orantigen-binding fragment thereof. In yet other embodiments, themonoclonal antibody or antigen-binding fragment thereof is a fully humanantibody or antigen-binding fragment thereof. The monoclonal antibodycan be of any isotype, such as a human IgG1, IgG2, IgG3, or IgG4. In oneparticular embodiment, the monoclonal antibody is a human IgG1 antibody.In another particular embodiment, the monoclonal antibody is a humanIgG2 antibody. The monoclonal antibody may comprise a light chain thatcomprises a human kappa constant region. In some embodiments, the humankappa constant region comprises the sequence of SEQ ID NO: 318 or SEQ IDNO: 319. Thus, the anti-PAC1 antibodies or antigen-binding fragments ofthe invention may comprise a light chain that comprises any of the lightchain variable region sequences listed in Table 1A fused to a humankappa constant region comprising the sequence of SEQ ID NO: 318 or SEQID NO: 319. In other embodiments, the monoclonal antibody may comprise alight chain that comprises a human lambda constant region. In certainembodiments, the human lambda constant region comprises the sequence ofSEQ ID NO: 315. Thus, in some embodiments, the anti-PAC1 antibodies orantigen-binding fragments of the invention may comprise a light chainthat comprises any of the light chain variable region sequences listedin Table 1A fused to a human lambda constant region comprising thesequence of SEQ ID NO: 315.

In certain embodiments, the anti-PAC1 antibodies or antigen-bindingfragments of the invention may contain one or more modifications thataffect the glycosylation of the antibody or antigen-binding fragment. Insome embodiments, the antibody or antigen-binding fragment comprises oneor more mutations to reduce or eliminate glycosylation. In suchembodiments, the aglycosylated antibody may comprise a mutation at aminoacid position N297 (according to the EU numbering scheme), such as aN297G mutation, in its heavy chain. The aglycosylated antibody maycomprise further mutations to stabilize the antibody structure. Suchmutations can include pairs of cysteine substitutions, such as A287C andL306C, V259C and L306C, R292C and V302C, and V323C and I332C (amino acidpositions according to the EU numbering scheme). In one embodiment, theaglycosylated antibody comprises R292C and V302C mutations (according tothe EU numbering scheme) in its heavy chain. In certain embodiments, theaglycosylated anti-PAC1 antibody comprises a heavy chain constant regioncomprising the amino acid sequence of SEQ ID NO: 324 or SEQ ID NO: 325.

The present invention also includes isolated polynucleotides andexpression vectors encoding the anti-PAC1 antibodies and antigen-bindingfragments described herein as well as host cells, such as CHO cells,comprising the encoding polynucleotides and expression vectors. Incertain embodiments, the present invention includes methods forproducing the anti-PAC1 antibodies and antigen-binding fragmentsdescribed herein. In one embodiment, the method comprises culturing ahost cell comprising an expression vector encoding the anti-PAC1antibody or antigen-binding fragment under conditions that allowexpression of the antibody or antigen-binding fragment, and recoveringthe antibody or antigen-binding fragment from the culture medium or hostcell.

The anti-PAC1 antibodies or antigen-binding fragments described hereincan be used in the manufacture of a pharmaceutical composition ormedicament for the treatment or prevention of conditions associated withPAC1 biological activity, such as headache, migraine, cluster headache,and vasomotor symptoms. Thus, the present invention also provides apharmaceutical composition comprising an anti-PAC1 antibody orantigen-binding fragment described herein and a pharmaceuticallyacceptable excipient. The pharmaceutical compositions can be used in anyof the methods described herein.

In certain embodiments, the present invention provides methods fortreating or preventing a headache condition in a patient in need thereofcomprising administering to the patient an effective amount of ananti-PAC1 antibody or antigen-binding fragment described herein. In someembodiments, the headache condition to be treated or prevented with themethods of the invention is migraine. The migraine can be episodicmigraine or chronic migraine. In other embodiments, the headachecondition to be treated or prevented with the methods of the inventionis cluster headache. In certain embodiments, the methods provideprophylactic treatment for these conditions.

In some embodiments of the methods of the invention, the methodscomprise administering a second headache therapeutic agent to thepatient in combination with an anti-PAC1 antibody or antigen-bindingfragment of the invention. The second headache therapeutic agent can bean acute headache therapeutic agent, such as a serotonin receptoragonist (e.g. agonist of a 5HT_(1B), 5HT_(1D), and/or 5HT_(1F) serotoninreceptor). In some embodiments, the acute headache therapeutic agent isa triptan, ergotamine, non-steroidal anti-inflammatory drug, or anopioid. In other embodiments, the second headache therapeutic agent tobe administered in combination with an anti-PAC1 antibody orantigen-binding fragment of the invention is a prophylactic headachetherapeutic agent, such as an antiepileptic, a beta-blocker, ananti-depressant, or onabotulinum toxin A. The second headachetherapeutic agent may be administered to the patient before, after, orconcurrently with an anti-PAC1 antibody or antigen-binding fragment ofthe invention.

In certain embodiments of the methods of the invention, the methodscomprise administering a CGRP pathway antagonist to the patient incombination with an anti-PAC1 antibody or antigen-binding fragment ofthe invention. The CGRP pathway antagonist can be an antagonist of thehuman CGRP receptor, such as an antibody that specifically binds to thehuman CGRP receptor. In one embodiment, the CGRP pathway antagonistadministered in combination with an anti-PAC1 antibody orantigen-binding fragment of the invention is erenumab. In otherembodiments, the CGRP pathway antagonist can be an antagonist of theCGRP ligand, such as an antibody that specifically binds to human α-CGRPand/or β-CGRP. In one such embodiment, the CGRP pathway antagonistadministered in combination with an anti-PAC1 antibody orantigen-binding fragment of the invention is fremanezumab. In anothersuch embodiment, the CGRP pathway antagonist administered in combinationwith an anti-PAC1 antibody or antigen-binding fragment of the inventionis galcanezumab. In yet another such embodiment, the CGRP pathwayantagonist administered in combination with an anti-PAC1 antibody orantigen-binding fragment of the invention is eptinezumab.

The present invention also includes methods of inhibiting vasodilationin a patient in need thereof. In one embodiment, the method comprisesadministering to the patient an effective amount of any of the anti-PAC1antibodies or antigen-binding fragments described herein. In someembodiments, the patient in need of treatment has a headache condition,such as migraine or cluster headache. In other embodiments, the patientin need of treatment has vasomotor symptoms (e.g. hot flashes, facialflushing, sweating, and night sweats), such as those associated withmenopause.

The use of the anti-PAC1 antibodies or antigen-binding fragments in anyof the methods disclosed herein or for preparation of medicaments foradministration according to any of the methods disclosed herein isspecifically contemplated. For instance, the present invention includesan anti-PAC1 antibody or antigen-binding fragment for use in a methodfor treating or preventing a headache condition in a patient in needthereof. The headache condition includes migraine (e.g. episodic andchronic migraine) and cluster headache. In some embodiments, the presentinvention provides an anti-PAC1 antibody or antigen-binding fragment foruse in a method for inhibiting vasodilation in a patient in needthereof. In such embodiments, the patient may be diagnosed with or havea headache condition. In other embodiments, the present inventionprovides an anti-PAC1 antibody or antigen-binding fragment for use in amethod for inhibiting activation of human PAC1 receptor in a patienthaving a headache condition. The headache condition may be migraine(e.g. episodic or chronic migraine) or cluster headache.

The present invention also includes the use of an anti-PAC1 antibody orantigen-binding fragment in the preparation of a medicament for treatingor preventing a headache condition in a patient in need thereof. Theheadache condition includes migraine (e.g. episodic and chronicmigraine) and cluster headache. In certain embodiments, the presentinvention encompasses the use of an anti-PAC1 antibody orantigen-binding fragment in the preparation of a medicament forinhibiting vasodilation in a patient in need thereof. In suchembodiments, the patient may be diagnosed with or have a headachecondition. In other embodiments, the present invention includes the useof an anti-PAC1 antibody or antigen-binding fragment in the preparationof a medicament for inhibiting activation of human PAC1 receptor in apatient having a headache condition. The headache condition may bemigraine (e.g. episodic or chronic migraine) or cluster headache.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a front view of the crystal structure of the complex betweenhuman PAC1 extracellular domain (ECD) and the Fab fragment of the 29G4v9antibody. VL=light chain variable region; CL=light chain constantregion; VH=heavy chain variable region; and CH1=heavy chain CH1 constantregion.

FIG. 1B is a side view of the crystal structure of the complex betweenhuman PAC1 ECD and the Fab fragment of the 29G4v9 antibody. The viewdepicts the structure shown in FIG. 1A rotated 90° to the left. In thisview, the light chain variable region (VL) is positioned behind theheavy chain variable region (VH), and the light chain constant region(CL) is positioned behind the heavy chain CH1 constant region.

FIG. 2A is an expanded view of the interface between the human PAC1 ECDand the light chain CDR1 (amino acids 24 to 34 of SEQ ID NO: 3) of the29G4v9 Fab. Zone 1 contains Glu120 and Asp121 residues of human PAC1 ECD(SEQ ID NO: 1), whereas Zone 3 contains the Phe127 residue of human PAC1ECD.

FIG. 2B is an expanded view of the interface between the human PAC1 ECDand Arg93 residue in the light chain CDR3 of the 29G4v9 Fab.

FIG. 3A is an expanded view of the interface between the human PAC1 ECDand heavy chain CDR1 amino acids Arg31 and Phe32 of the 29G4v9 Fab. Thetwo heavy chain CDR1 amino acids lie on either side of the Phe131residue of human PAC1 ECD.

FIG. 3B is an expanded view of the interface between a region of thehuman PAC1 ECD containing amino acid residues Asn60 and Ile61 (relativeto SEQ ID NO: 1) and heavy chain CDR2 amino acids Tyr53, Asp54, andGly56 of the 29G4v9 Fab.

FIG. 3C is an expanded view of the interface between the human PAC1 ECDand heavy chain CDR3 amino acids Val102, Leu103, and Thr104 of the29G4v9 Fab.

FIG. 4 is a schematic of the selection process for improved bindingmutants from a yeast-displayed antibody Fab mutant library.

FIG. 5 is a schematic of the binding off-rate driven selection processfor high affinity binding mutants from a yeast-displayed library.

FIG. 6 shows the inhibitory effect of anti-PAC1 antibodies onmaxadilan-induced increase in dermal blood flow in rats. One of sevenantibodies (420653, 420845, 420943, 421873, 420889 (PL-50347), 421091(PL-50350), and 421051 (PL-50351)) was administered to ratsintravenously at a dose of 0.1 mg/kg or 0.3 mg/kg twenty-four hoursprior to challenge with 10 ng maxadilan (intradermal injection). Dermalblood flow was assessed 30 minutes following maxadilan challenge withlaser Doppler imaging. *p<0.05, **p<0.01 compared to the vehicle groupwith One-Way ANOVA followed by Dunnett's MCT.

FIG. 7A shows the dose-dependent effect of anti-PAC1 antibody 420653 onmaxadilan-induced increase in dermal blood flow in rats. The antibodywas administered to rats intravenously at one of seven doses rangingfrom 0.01 mg/kg to 3 mg/kg twenty-four hours prior to challenge with 10ng maxadilan (intradermal injection). Dermal blood flow was assessed 30minutes following maxadilan challenge with laser Doppler imaging.*p<0.05, ****p<0.0001 compared to the vehicle group with One-Way ANOVAfollowed by Dunnett's MCT.

FIG. 7B shows the dose-dependent effect of anti-PAC1 antibody 420845 onmaxadilan-induced increase in dermal blood flow in rats. The antibodywas administered to rats intravenously at one of five doses ranging from0.01 mg/kg to 3 mg/kg twenty-four hours prior to challenge with 10 ngmaxadilan (intradermal injection). Dermal blood flow was assessed 30minutes following maxadilan challenge with laser Doppler imaging.****p<0.0001 compared to the vehicle group with One-Way ANOVA followedby Dunnett's MCT.

FIG. 7C shows the dose-dependent effect of anti-PAC1 antibody 420943 onmaxadilan-induced increase in dermal blood flow in rats. The antibodywas administered to rats intravenously at one of six doses ranging from0.1 mg/kg to 30 mg/kg twenty-four hours prior to challenge with 10 ngmaxadilan (intradermal injection). Dermal blood flow was assessed 30minutes following maxadilan challenge with laser Doppler imaging.****p<0.0001 compared to the vehicle group with One-Way ANOVA followedby Dunnett's MCT.

FIG. 7D shows the dose-dependent effect of anti-PAC1 antibody 421873 onmaxadilan-induced increase in dermal blood flow in rats. The antibodywas administered to rats intravenously at one of five doses ranging from0.3 mg/kg to 30 mg/kg twenty-four hours prior to challenge with 10 ngmaxadilan (intradermal injection). Dermal blood flow was assessed 30minutes following maxadilan challenge with laser Doppler imaging.*p<0.05, ****p<0.0001 compared to the vehicle group with One-Way ANOVAfollowed by Dunnett's MCT.

FIG. 8A is the serum concentration-time profile for anti-PAC1 antibodies420653, 420845, 420943, and 421873 following a single intravenous doseof 1 mg/kg in rats.

FIG. 8B is the serum concentration-time profile for anti-PAC1 antibodies420653, 420845, 420943, and 421873 following a single intravenous doseof 5 mg/kg in rats.

FIG. 8C is the serum concentration-time profile for anti-PAC1 antibodies420653, 420845, 420943, and 421873 following a single intravenous doseof 25 mg/kg in rats.

FIG. 9 is the serum concentration-time profile for anti-PAC1 antibodies420653, 420845, 420943, 421873, and 29G4v22 following a singleintravenous dose of 10 mg/kg in cynomolgus monkeys.

FIGS. 10A and 10B show the time-course of the inhibitory effects ofanti-PAC1 antibodies 420653 and 29G4v22 on maxadilan-induced increase indermal blood flow in cynomolgus monkeys. Twenty-four cynomolgus monkeyswere given a single i.v. bolus injection of antibody 420653 at 0.1 mg/kgor 3 mg/kg or antibody 29G4v22 at 10 mg/kg at Day 0. On Days 2, 4, 7,10, 14, 21, 28, and 36 following antibody dosing, post-maxadilanresponses were measured. In each case, dermal blood flow was measured bylaser Doppler imaging 30 minutes following 1 ng maxadilan intradermalinjection. All data are expressed as the mean±standard error of themean. FIG. 10A shows the % change from baseline in dermal blood flowinduced by intradermal injection of maxadilan at the indicated daysfollowing antibody treatment. *p<0.05, **p<0.01, ***p<0.001 compared toDay 0 within the same treatment group by one-way ANOVA followed byBonferroni's Multiple Comparison Test. Eight animals per group exceptfor Day 36 in which four animals were tested with antibody 420653 at 3mg/kg as denoted by the {circumflex over ( )} symbol. FIG. 10B shows theinhibitory effect of antibody treatment on maxadilan-induced increase indermal blood flow expressed as % inhibition. #p<0.05, ##p<0.01,###p<0.001 comparison between antibody 420653 at 3 mg/kg and antibody29G4v22 at 10 mg/kg at each time point by two-tailed Unpaired t-test.

DETAILED DESCRIPTION

The present invention relates to isolated antibodies and antigen-bindingfragments thereof that specifically bind to pituitary adenylatecyclase-activating polypeptide type I receptor (PAC1), particularlyhuman PAC1. The antibodies of the invention have enhanced inhibitorypotency against human PAC1 as compared to previously described anti-PAC1antagonist antibodies. The antibodies of the invention also cross-reactwith the rat PAC1 receptor and the cynomolgus monkey PAC1 receptor,thereby allowing for preclinical in vivo evaluation of the antibodies inthese species.

Human PAC1 is a 468 amino acid protein (NCBI Reference SequenceNP_001109.2) encoded by the ADCYAP1R1 gene on chromosome 7. The humanPAC1 receptor is a G protein-coupled receptor that is positively coupledto adenylate cyclase. Activation of the human PAC1 receptor by itsendogenous ligands (e.g. PACAP38 or PACAP27) results in an increase inintracellular cyclic AMP (cAMP). The amino acid sequence for human PAC1is provided below as SEQ ID NO: 1.

1 MAGVVHVSLA ALLLLPMAPA MHSDCIFKKE QAMCLEKIQR ANELMGFNDS SPGCPGMWDN 61ITCWKPAHVG EMVLVSCPEL FRIFNPDQVW ETETIGESDF GDSNSLDLSD MGVVSRNCTE 121DGWSEPFPHY FDACGFDEYE SETGDQDYYY LSVKALYTVG YSTSLVTLTT AMVILCRFRK 181LHCTRNFIHM NLFVSFMLRA ISVFIKDWIL YAEQDSNHCF ISTVECKAVM VFFHYCVVSN 241YFWLFIEGLY LFTLLVETFF PERRYFYWYT IIGWGTPTVC VTVWATLRLY FDDTGCWDMN 301DSTALWWVIK GPVVGSIMVN FVLFIGIIVI LVQKLQSPDM GGNESSIYLR LARSTLLLIP 361LFGIHYTVFA FSPENVSKRE RLVFELGLGS FQGFVVAVLY CFLNGEVQAE IKRKWRSWKV 421NRYFAVDFKH RHPSLASSGV NGGTQLSILS KSSSQIRMSG LPADNLAT

Amino acids 1 to 23 of the human PAC1 protein (SEQ ID NO: 1) constitutea signal peptide, which is generally removed from the mature protein.The mature human PAC1 protein has the basic structure of a Gprotein-coupled receptor consisting of a seven-transmembrane domain, anextracellular domain composed of an N-terminal region and threeextracellular loops, three intracellular loops, and a C-terminalcytoplasmic domain. The N-terminal extracellular domain is approximatelyat amino acids 24-153 of SEQ ID NO: 1, and the first of seventransmembrane domains begins at amino acid 154 of SEQ ID NO: 1. TheC-terminal cytoplasmic domain is located approximately at amino acids397-468 of SEQ ID NO: 1. See Blechman and Levkowitz, Front. Endocrinol.,Vol. 4 (55): 1-19, 2013 for location of domains within the amino acidsequence. The terms “human PAC1,” “human PAC1 receptor,” “hPAC1,” and“hPAC1 receptor” are used interchangeably and can refer to a polypeptideof SEQ ID NO: 1, a polypeptide of SEQ ID NO: 1 minus the signal peptide(amino acids 1 to 23), allelic variants of human PAC1, or splicevariants of human PAC1.

The present invention provides antibodies that specifically bind tohuman PAC1. An “antibody” is a protein that comprises an antigen-bindingfragment that specifically binds to an antigen, and a scaffold orframework portion that allows the antigen-binding fragment to adopt aconformation that promotes binding of the antibody to the antigen. Asused herein, the term “antibody” generally refers to a tetramericimmunoglobulin protein comprising two light chain polypeptides (about 25kDa each) and two heavy chain polypeptides (about 50-70 kDa each). Theterm “light chain” or “immunoglobulin light chain” refers to apolypeptide comprising, from amino terminus to carboxyl terminus, asingle immunoglobulin light chain variable region (VL) and a singleimmunoglobulin light chain constant domain (CL). The immunoglobulinlight chain constant domain (CL) can be a human kappa (κ) or humanlambda (λ) constant domain. The term “heavy chain” or “immunoglobulinheavy chain” refers to a polypeptide comprising, from amino terminus tocarboxyl terminus, a single immunoglobulin heavy chain variable region(VH), an immunoglobulin heavy chain constant domain 1 (CH1), animmunoglobulin hinge region, an immunoglobulin heavy chain constantdomain 2 (CH2), an immunoglobulin heavy chain constant domain 3 (CH3),and optionally an immunoglobulin heavy chain constant domain 4 (CH4).Heavy chains are classified as mu (μ), delta (Δ), gamma (γ), alpha (α),and epsilon (ε), and define the antibody's isotype as IgM, IgD, IgG,IgA, and IgE, respectively. The IgG-class and IgA-class antibodies arefurther divided into subclasses, namely, IgG1, IgG2, IgG3, and IgG4, andIgA1 and IgA2, respectively. The heavy chains in IgG, IgA, and IgDantibodies have three constant domains (CH1, CH2, and CH3), whereas theheavy chains in IgM and IgE antibodies have four constant domains (CH1,CH2, CH3, and CH4). The immunoglobulin heavy chain constant domains canbe from any immunoglobulin isotype, including subtypes. The antibodychains are linked together via inter-polypeptide disulfide bonds betweenthe CL domain and the CH1 domain (i.e. between the light and heavychain) and between the hinge regions of the two antibody heavy chains.

The present invention also includes antigen-binding fragments of theanti-PAC1 antibodies described herein. An “antigen-binding fragment,”used interchangeably herein with “binding fragment” or “fragment,” is aportion of an antibody that lacks at least some of the amino acidspresent in a full-length heavy chain and/or light chain, but which isstill capable of specifically binding to an antigen. An antigen-bindingfragment includes, but is not limited to, a single-chain variablefragment (scFv), a nanobody (e.g. VH domain of camelid heavy chainantibodies; VHH fragment, see Cortez-Retamozo et al., Cancer Research,Vol. 64:2853-57, 2004), a Fab fragment, a Fab′ fragment, a F(ab)₂fragment, a Fv fragment, a Fd fragment, and a complementaritydetermining region (CDR) fragment, and can be derived from any mammaliansource, such as human, mouse, rat, rabbit, or camelid. Antigen-bindingfragments may compete for binding of a target antigen with an intactantibody and the fragments may be produced by the modification of intactantibodies (e.g. enzymatic or chemical cleavage) or synthesized de novousing recombinant DNA technologies or peptide synthesis. In someembodiments, the antigen-binding fragment comprises at least one CDRfrom an antibody that binds to the antigen, for example, the heavy chainCDR3 from an antibody that binds to the antigen. In other embodiments,the antigen-binding fragment comprises all three CDRs from the heavychain of an antibody that binds to the antigen or all three CDRs fromthe light chain of an antibody that binds to the antigen. In still otherembodiments, the antigen-binding fragment comprises all six CDRs from anantibody that binds to the antigen (three from the heavy chain and threefrom the light chain).

The term “isolated molecule” (where the molecule is, for example, apolypeptide, a polynucleotide, an antibody, or antigen-binding fragment)is a molecule that by virtue of its origin or source of derivation (1)is not associated with naturally associated components that accompany itin its native state, (2) is substantially free of other molecules fromthe same species (3) is expressed by a cell from a different species, or(4) does not occur in nature. Thus, a molecule that is chemicallysynthesized, or expressed in a cellular system different from the cellfrom which it naturally originates, will be “isolated” from itsnaturally associated components. A molecule also may be renderedsubstantially free of naturally associated components by isolation,using purification techniques well known in the art. Molecule purity orhomogeneity may be assayed by a number of means well known in the art.For example, the purity of a polypeptide sample may be assayed usingpolyacrylamide gel electrophoresis and staining of the gel to visualizethe polypeptide using techniques well known in the art. For certainpurposes, higher resolution may be provided by using HPLC or other meanswell known in the art for purification.

In certain embodiments of the invention, the antibodies orantigen-binding fragments thereof specifically bind to human PAC1. Anantibody or antigen-binding fragment thereof “specifically binds” to atarget antigen when it has a significantly higher binding affinity for,and consequently is capable of distinguishing, that antigen compared toits affinity for other unrelated proteins, under similar binding assayconditions. Antibodies or antigen-binding fragments that specificallybind an antigen may have an equilibrium dissociation constant(K_(D))≤1×10⁻⁶ M. The antibody or binding fragment specifically bindsantigen with “high affinity” when the K_(D) is ≤1×10⁻⁸M. In oneembodiment, the antibodies or binding fragments of the invention bind tohuman PAC1 with a K_(D) of ≤5×10⁻⁹M. In another embodiment, theantibodies or binding fragments of the invention bind to human PAC1 witha K_(D) of ≤1×10⁻⁹M. In yet another embodiment, the antibodies orbinding fragments of the invention bind to human PAC1 with a K_(D) of≤5×10⁻¹⁰ M. In another embodiment, the antibodies or binding fragmentsof the invention bind to human PAC1 with a K_(D) of ≤1×10⁻¹⁰ M. Incertain embodiments, the antibodies or binding fragments of theinvention bind to human PAC1 with a K_(D) of ≤5×10⁻¹¹ M. In otherembodiments, the antibodies or binding fragments of the invention bindto human PAC1 with a K_(D) of ≤1×10⁻¹¹M. In one particular embodiment,the antibodies or binding fragments of the invention bind to human PAC1with a K_(D) of ≤5×10⁻¹² M. In another particular embodiment, theantibodies or binding fragments of the invention bind to human PAC1 witha K_(D) of ≤1×10⁻¹² M.

Affinity is determined using a variety of techniques, an example ofwhich is an affinity ELISA assay. In various embodiments, affinity isdetermined by a surface plasmon resonance assay (e.g., BIAcore®-basedassay). Using this methodology, the association rate constant (ka in M⁻¹s⁻¹) and the dissociation rate constant (k_(d) in s⁻¹) can be measured.The equilibrium dissociation constant (K_(D) in M) can then becalculated from the ratio of the kinetic rate constants (k_(d)/k_(a)).In some embodiments, affinity is determined by a kinetic method, such asa Kinetic Exclusion Assay (KinExA) as described in Rathanaswami et al.Analytical Biochemistry, Vol. 373:52-60, 2008. Using a KinExA assay, theequilibrium dissociation constant (K_(D) in M) and the association rateconstant (k_(a) in M⁻¹ s⁻¹) can be measured. The dissociation rateconstant (k_(d) in s⁻¹) can be calculated from these values(K_(D)×k_(a)). In other embodiments, affinity is determined by abio-layer interferometry method, such as that described in Kumaraswamyet al., Methods Mol. Biol., Vol. 1278:165-82, 2015 and employed inOctet® systems (Pall ForteBio). The kinetic (k_(a) and k_(d)) andaffinity (K_(D)) constants can be calculated in real-time using thebio-layer interferometry method. In some embodiments, the antibodies orbinding fragments described herein exhibit desirable characteristicssuch as binding avidity as measured by k_(d) (dissociation rateconstant) for human PAC1 of about 10⁻², 10⁻³, 10⁻⁴, 10⁻⁵, 10⁻⁶, 10⁻⁷,10⁻⁸, 10⁻⁹, 10⁻¹⁰ s⁻¹ or lower (lower values indicating higher bindingavidity), and/or binding affinity as measured by K_(D) (equilibriumdissociation constant) for human PAC1 of about 10⁻⁸, 10⁻⁹, 10⁻¹⁰, 10⁻¹¹,10⁻¹² M or lower (lower values indicating higher binding affinity).

Preferably, the antibodies or binding fragments of the invention do notsignificantly bind to or cross-react with other members of thesecretin/glucagon receptor family, such as human VPAC1 receptor (NCBIReference Sequence NP_004615.2) and human VPAC2 receptor (NCBI ReferenceSequence NP_003373.2). As used herein, an antibody or binding fragmentdoes “not significantly bind” to a target antigen when it has a bindingaffinity for that antigen that is comparable to its affinity for otherunrelated proteins, under similar binding assay conditions. Antibodiesor binding fragments that do not significantly bind to a target antigenmay also include those proteins that do not generate a statisticallydifferent signal than a negative control in an affinity assay, such asthose described herein, for the target antigen. By way of example, anantibody, which produces a signal value in an ELISA- or a BIAcore®-basedassay for determining binding to human VPAC1 that is not statisticallydifferent from the signal value produced with a negative control (e.g.buffer solution without antibody), would be considered to notsignificantly bind to human VPAC1. Antibodies or binding fragments thatdo not significantly bind an antigen may have an equilibriumdissociation constant (K_(D)) for that antigen greater than 1×10⁻⁶ M,greater than 1×10⁻⁵ M, greater than 1×10⁻⁴ M, or greater than 1×10⁻³ M.Thus, in certain embodiments, the antibodies and binding fragments ofthe invention selectively bind to human PAC1 relative to human VPAC1 andhuman VPAC2. In other words, the antibodies and binding fragments of theinvention do not significantly bind to human VPAC1 or human VPAC2.

The antibodies and antigen-binding fragments of the invention mayinhibit, interfere with, or modulate one or more biological activitiesof the human PAC1 receptor. Biological activities of the human PAC1receptor include, but are not limited to, induction of PACAP-mediatedreceptor signal transduction pathways, induction of vasodilation, andinhibition of vasoconstriction. In some embodiments, the antibodies orbinding fragments of the invention inhibit binding of PACAP (e.g.PACAP38 or PACAP27) to the human PAC1 receptor. “Inhibition of binding”occurs when an excess of antibodies or binding fragments reduces thequantity of human PAC1 receptor bound to PACAP, or vice versa, forexample, by at least about 40%, about 50%, about 60%, about 70%, about80%, about 85%, about 90%, about 95%, about 97%, about 99% or more, forexample by measuring binding in an in vitro competitive binding assay.Inhibitory constants (Ki), which are indicative of how potent theantibodies or antigen-binding fragments of the invention are atpreventing binding of PACAP to human PAC1 receptor, can be calculatedfrom such competitive binding assays. By way of example, a radioactiveisotope (e.g. ¹²⁵I) is attached to the receptor ligand (e.g. PACAP38)and the assay measures the binding of the radiolabeled ligand to humanPAC1 receptor in increasing concentrations of the anti-PAC1 antibody orbinding fragment thereof. The Ki value can be calculated using theequation Ki=IC50/(1+([L]/Kd)), where [L] is the concentration of theradioligand used (e.g., ¹²⁵I-labeled PACAP38) and Kd is the dissociationconstant of the radioligand. See, e.g., Keen M, MacDermot J (1993)Analysis of receptors by radioligand binding. In: Wharton J, Polak J M(eds) Receptor autoradiography, principles and practice. OxfordUniversity Press, Oxford. The lower the value of Ki for an antagonist,the more potent the antagonist is. In some embodiments, the antibodiesor antigen-binding fragments thereof of the invention compete forbinding to the human PAC1 receptor with a radiolabeled PACAP ligand witha Ki of ≤1 nM. In other embodiments, the antibodies or antigen-bindingfragments thereof of the invention compete for binding to the human PAC1receptor with a radiolabeled PACAP ligand with a Ki of ≤500 pM. In yetother embodiments, the antibodies or antigen-binding fragments thereofof the invention compete for binding to the human PAC1 receptor with aradiolabeled PACAP ligand with a Ki of ≤200 pM. In certain otherembodiments, the antibodies or antigen-binding fragments thereof of theinvention compete for binding to the human PAC1 receptor with aradiolabeled PACAP ligand with a Ki of ≤100 pM.

In certain embodiments, the antibodies and antigen-binding fragments ofthe invention inhibit ligand-induced activation of the human PAC1receptor. The ligand can be an endogenous ligand of the receptor, suchas PACAP38 or PACAP27, or the ligand can be another known agonist of thereceptor, such as maxadilan. Maxadilan is a 65 amino acid peptideoriginally isolated from the sand fly that is exquisitely selective forPAC1 compared with VPAC1 or VPAC2, and can thus be used as aPAC1-selective agonist (Lerner et al., J Biol Chem., Vol.266(17):11234-11236, 1991; Lerner et al., Peptides, Vol. 28(9):1651-1654, 2007). Various assays for assessing activation of PAC1receptors are known in the art and include cell-based assays measuringligand-induced calcium mobilization and cAMP production. An exemplarycell-based cAMP assay is described in Example 3. Other suitable PAC1receptor activation assays are described in Dickson et al., Ann. N. Y.Acad. Sci., Vol. 1070:239-42, 2006; Bourgault et al., J. Med. Chem.,Vol. 52: 3308-3316, 2009; and U.S. Patent Publication No. 2011/0229423,all of which are hereby incorporated by reference in their entireties.

The inhibitory activity of the antibodies or antigen-binding fragmentson PAC1 receptor activation can be quantitated by calculating an IC50 inany functional assay for the receptor, such as those described above. An“IC50” is the dose/concentration required to achieve 50% inhibition of abiological or biochemical function. With radioactive ligands, IC50 isthe concentration of a competing ligand that displaces 50% of thespecific binding of the radioligand. The IC50 of any particularsubstance or antagonist can be determined by constructing adose-response curve and examining the effect of different concentrationsof the drug or antagonist on reversing agonist activity in a particularfunctional assay. IC50 values can be calculated for a given antagonistor drug by determining the concentration needed to inhibit half of themaximum biological response of the agonist. Thus, the IC50 value for anyanti-PAC1 antibody or binding fragment thereof of the invention can becalculated by determining the concentration of the antibody or bindingfragment needed to inhibit half of the maximum biological response ofthe ligand (e.g. PACAP27, PACAP38, or maxadilan) in activating the humanPAC1 receptor in any functional assay, such as the cAMP assay describedin the Examples. An anti-PAC1 antibody or binding fragment thereof thatinhibits ligand-induced (e.g. PACAP-induced) activation of the PAC1receptor is understood to be a neutralizing or antagonist antibody orbinding fragment of the PAC1 receptor.

In certain embodiments, the antibodies or antigen-binding fragments ofthe invention inhibit PACAP-induced (PACAP38- or PACAP27-induced)activation of the human PAC1 receptor. For instance, the antibodies orantigen-binding fragments may inhibit PACAP-induced activation of thehuman PAC1 receptor with an IC50 less than about 10 nM, less than about8 nM, less than about 5 nM, less than about 3 nM, less than about 1 nM,less than about 800 pM, less than about 500 pM, less than about 400 pM,less than about 300 pM, less than about 200 pM, or less than about 100pM as measured by a cell-based calcium mobilization assay or cAMP assay.In one particular embodiment, the antibodies or antigen-bindingfragments of the invention inhibit PACAP-induced activation of the humanPAC1 receptor with an IC50 less than about 5 nM as measured by acell-based cAMP assay. In another particular embodiment, the antibodiesor antigen-binding fragments of the invention inhibit PACAP-inducedactivation of the human PAC1 receptor with an IC50 less than about 1 nMas measured by a cell-based cAMP assay. In still another particularembodiment, the antibodies or antigen-binding fragments of the inventioninhibit PACAP-induced activation of the human PAC1 receptor with an IC50less than about 500 pM as measured by a cell-based cAMP assay. Inanother embodiment, the antibodies or antigen-binding fragments of theinvention inhibit PACAP-induced activation of the human PAC1 receptorwith an IC50 less than about 300 pM as measured by a cell-based cAMPassay. In some embodiments, the antibodies or antigen-binding fragmentsof the invention inhibit PACAP-induced activation of the human PAC1receptor with an IC50 between about 0.1 nM and about 1 nM as measured bya cell-based cAMP assay. In other embodiments, the antibodies orantigen-binding fragments of the invention inhibit PACAP-inducedactivation of the human PAC1 receptor with an IC50 between about 50 pMand about 500 pM as measured by a cell-based cAMP assay.

In some embodiments, the antibodies or antigen-binding fragments of theinvention bind to and inhibit PAC1 receptors from other species. Forinstance, the antibodies or antigen-binding fragments bind to andinhibit the cynomolgus monkey PAC1 receptor (NCBI Reference SequenceXP_015303041.1). In such embodiments, the antibodies or antigen-bindingfragments inhibit PACAP-induced activation of the cynomolgus monkey PAC1receptor with an IC50 less than about 10 nM, less than about 8 nM, lessthan about 5 nM, less than about 3 nM, less than about 1 nM, less thanabout 800 pM, less than about 500 pM, less than about 400 pM, less thanabout 300 pM, less than about 200 pM, or less than about 100 pM asmeasured by a cell-based calcium mobilization assay or cAMP assay. Inone embodiment, the antibodies or antigen-binding fragments of theinvention inhibit PACAP-induced activation of the cynomolgus monkey PAC1receptor with an IC50 less than about 1 nM as measured by a cell-basedcAMP assay. In another embodiment, the antibodies or antigen-bindingfragments of the invention inhibit PACAP-induced activation of thecynomolgus monkey PAC1 receptor with an IC50 less than about 500 pM asmeasured by a cell-based cAMP assay. In yet another embodiment, theantibodies or antigen-binding fragments of the invention inhibitPACAP-induced activation of the cynomolgus monkey PAC1 receptor with anIC50 between about 0.1 nM and about 1 nM as measured by a cell-basedcAMP assay. In still another embodiment, the antibodies orantigen-binding fragments of the invention inhibit PACAP-inducedactivation of the cynomolgus monkey PAC1 receptor with an IC50 betweenabout 50 pM and about 500 pM as measured by a cell-based cAMP assay.

In certain embodiments, the antibodies or antigen-binding fragments bindto and inhibit the rat PAC1 receptor (NCBI Reference SequenceNP_598195.1). In these embodiments, the antibodies or antigen-bindingfragments may inhibit PACAP-induced activation of the rat PAC1 receptorwith an IC50 less than about 10 nM, less than about 8 nM, less thanabout 5 nM, less than about 3 nM, less than about 1 nM, less than about800 pM, less than about 500 pM, less than about 400 pM, less than about300 pM, less than about 200 pM, or less than about 100 pM as measured bya cell-based calcium mobilization assay or cAMP assay. In oneembodiment, the antibodies or antigen-binding fragments of the inventioninhibit PACAP-induced activation of the rat PAC1 receptor with an IC50less than about 10 nM as measured by a cell-based cAMP assay. In anotherembodiment, the antibodies or antigen-binding fragments of the inventioninhibit PACAP-induced activation of the rat PAC1 receptor with an IC50less than about 5 nM as measured by a cell-based cAMP assay. In yetanother embodiment, the antibodies or antigen-binding fragments of theinvention inhibit PACAP-induced activation of the rat PAC1 receptor withan IC50 less than about 500 pM as measured by a cell-based cAMP assay.In still another embodiment, the antibodies or antigen-binding fragmentsof the invention inhibit PACAP-induced activation of the rat PAC1receptor with an IC50 less than about 300 pM as measured by a cell-basedcAMP assay. In some embodiments, the antibodies or antigen-bindingfragments of the invention inhibit PACAP-induced activation of the ratPAC1 receptor with an IC50 between about 0.1 nM and about 10 nM asmeasured by a cell-based cAMP assay. In still another embodiment, theantibodies or antigen-binding fragments of the invention inhibitPACAP-induced activation of the rat PAC1 receptor with an IC50 betweenabout 100 pM and about 2 nM as measured by a cell-based cAMP assay. Insome embodiments in which the antibodies or binding fragments of theinvention cross-react with PAC1 receptors from other species, theantibodies or binding fragments may inhibit PACAP-induced activation ofthe PAC1 receptor with comparable potencies. For example, an antibody orbinding fragment of the invention may inhibit PACAP-induced activationof the human PAC1 receptor with an IC50 similar to the IC50 for theantibody or binding fragment to inhibit PACAP-induced activation of thecynomolgus monkey or rat PAC1 receptor. Cross-reactivity to PAC1receptors of other species of the antibodies or binding fragments of theinvention can be advantageous as the antibodies or binding fragments canbe evaluated in additional pre-clinical animal models for therapeuticefficacy.

Generally, the antibodies or antigen-binding fragments of the inventiondo not significantly inhibit ligand-induced activation (e.g. PACAP38-,PACAP27-, or VIP-induced) of the human VPAC1 receptor or VPAC2 receptor.As used herein, an antibody or antigen-binding fragment would “notsignificantly inhibit” the activation of a receptor or binding of aligand to its receptor if there is no statistical difference betweenligand-induced receptor activation or ligand binding to the receptor inthe presence or absence of the antibody or antigen-binding fragment. Forexample, if the amount of cAMP production induced by PACAP or VIP incells expressing human VPAC1 receptor in the presence of an antibody orbinding fragment is not statistically different than the amount producedin the absence of the antibody or binding fragment, then the antibody orbinding fragment would be considered to not significantly inhibitPACAP/VIP-induced activation of the human VPAC1 receptor. Similarly, ifthe amount of PACAP or VIP bound to the human VPAC1 receptor in thepresence of excess antibody or binding fragment is not statisticallydifferent than the amount of PACAP or VIP bound to the receptor in theabsence of the antibody or binding fragment, then the antibody orbinding fragment would be considered to not significantly inhibit thebinding of PACAP or VIP to the human VPAC1 receptor. In certainembodiments, the antibodies or binding fragments of the inventioninhibit PACAP-induced activation of the human PAC1 receptor, but do notsignificantly inhibit PACAP-induced activation of the human VPAC1receptor or the human VPAC2 receptor. Thus, the antibodies and bindingfragments of the invention selectively inhibit the human PAC1 receptorrelative to the human VPAC1 receptor and the human VPAC2 receptor.

The antibodies and binding fragments of the invention may, in someembodiments, bind to a particular region or epitope of human PAC1. Asused herein, an “epitope” refers to any determinant capable of beingspecifically bound by an antibody or fragment thereof. An epitope is aregion of an antigen that is bound by, or interacts with, an antibody orbinding fragment that targets that antigen, and when the antigen is aprotein, includes specific amino acids that directly contact, orinteract with, the antibody or binding fragment. An epitope can beformed both by contiguous amino acids or non-contiguous amino acidsjuxtaposed by tertiary folding of a protein. A “linear epitope” is anepitope where an amino acid primary sequence comprises the recognizedepitope. A linear epitope typically includes at least 3 or 4 aminoacids, and more usually, at least 5, at least 6, or at least 7 aminoacids, for example, about 8 to about 10 amino acids in a uniquesequence. A “conformational epitope,” in contrast to a linear epitope,is a group of discontinuous amino acids (e.g., in a polypeptide, aminoacid residues that are not contiguous in the polypeptide's primarysequence but that, in the context of the polypeptide's tertiary andquaternary structure, are near enough to each other to be bound by anantibody or binding fragment thereof). Epitope determinants can includechemically active surface groupings of molecules such as amino acids,sugar side chains, phosphoryl or sulfonyl groups, and can have specificthree-dimensional structural characteristics, and/or specific chargecharacteristics. Generally, antibodies or binding fragments specific fora particular target molecule will preferentially recognize an epitope onthe target molecule in a complex mixture of proteins and/ormacromolecules.

In certain embodiments, the antibodies or antigen-binding fragments ofthe invention bind to human PAC1 at an epitope within the N-terminalextracellular domain (ECD) of human PAC1 (SEQ ID NO: 4). In relatedembodiments, the antibodies or antigen-binding fragments bind to humanPAC1 at an epitope within amino acids 24-153 of SEQ ID NO: 1. In otherrelated embodiments, the antibodies or antigen-binding fragments bind tohuman PAC1 at an epitope within amino acids 50-140 of SEQ ID NO: 1. Asdescribed in Example 1, a crystal structure of the complex of the humanPAC1 N-terminal ECD and the Fab region of an anti-PAC1 neutralizingantibody revealed key amino acids within the human PAC1 ECD thatcomprised the binding interface with the anti-PAC1 Fab. These coreinterface amino acids, all of which contained at least one non-hydrogenatom at a distance of 5 Å or less from a non-hydrogen atom in the Fab,include Asp59, Asn60, Ile61, Arg116, Asn117, Thr119, Asp121, Gly122,Trp123, Ser124, Glu125, Pro126, Phe127, Pro128, His129, Tyr130, Phe131,Asp132, and Gly135 (amino acid position numbers relative to SEQ ID NO:1). Thus, in some embodiments, the antibodies or binding fragments ofthe invention bind to human PAC1 at an epitope comprising one or moreamino acids selected from Asp59, Asn60, Ile61, Arg116, Asn117, Thr119,Glu120, Asp121, Gly122, Trp123, Ser124, Glu125, Pro126, Phe127, Pro128,His129, Tyr130, Phe131, Asp132, and Gly135 of SEQ ID NO: 1. In otherembodiments, the antibodies or binding fragments bind to human PAC1 atan epitope comprising at least amino acids Asn60, Ile61, Glu120, andAsp121 of SEQ ID NO: 1. In yet other embodiments, the antibodies orbinding fragments bind to human PAC1 at an epitope comprising at leastamino acids Asn60, Ile61, Glu120, Asp121, Phe127, and Phe131 of SEQ IDNO: 1. In certain other embodiments, the antibodies or binding fragmentsbind to human PAC1 at an epitope comprising all of the amino acidsselected from Asp59, Asn60, Ile61, Arg116, Asn117, Thr119, Glu120,Asp121, Gly122, Trp123, Ser124, Glu125, Pro126, Phe127, Pro128, His129,Tyr130, Phe131, Asp132, and Gly of SEQ ID NO: 1.

The crystal structure of the human PAC1 ECD-Fab complex described inExample 1 also revealed important residues in the CDRs of the heavy andlight chains of the Fab that interacted with the amino acids in thehuman PAC1 ECD, thereby identifying key amino acids in the paratope ofthe antibody. A “paratope” is the region of an antibody that recognizesand binds to the target antigen. Paratope residues include Gln27, Gly30,Arg31, and Ser32 in the light chain variable region (SEQ ID NO: 3) andArg31, Phe32, Tyr53, Asp54, Gly56 in the heavy chain variable region(SEQ ID NO: 2). Specific mutations of several of these residues in theparatope were designed to improve the interaction with the coreinterface residues (i.e. residues in the epitope) in the human PAC1 ECDresulting in enhanced binding affinity and inhibitory potency ascompared to the parental antibody (see Examples 1-3). Gln27, Gly30,Arg31, and Ser32 in the light chain variable region of SEQ ID NO: 3 orSEQ ID NO: 52 correspond to amino acids positions 29, 32, 39, and 40 inAHo numbering, respectively, and Arg31, Phe32, Tyr53, Asp54, Gly56 inthe heavy chain variable region of SEQ ID NO: 2 or SEQ ID NO: 191correspond to amino acid positions 33, 39, 60, 61, and 66 in AHonumbering, respectively. The AHo numbering scheme is a structure-basednumbering scheme, which introduces gaps in the CDR regions to minimizedeviation from the average structure of the aligned domains (Honeggerand Pluckthun, J. Mol. Biol. 309(3):657-670; 2001). In the AHo numberingscheme, structurally equivalent positions in different antibodies willhave the same residue number.

In some embodiments, the present invention provides an antibody orantigen-binding fragment thereof that specifically binds to human PAC1(SEQ ID NO: 1), wherein the antibody or antigen-binding fragment thereofcomprises: (i) a light chain variable region in which the amino acid atposition 29 according to AHo numbering is a basic amino acid thatinteracts with amino acids Glu120 or Asp121 of human PAC1, and (ii) aheavy chain variable region in which the amino acid at position 61according to AHo numbering is a hydrophobic, basic, or neutralhydrophilic amino acid that interacts with amino acids Asn60 or Ile61 ofhuman PAC1. As used herein, one amino acid is said to “interact” withanother amino acid when one or more atoms in one amino acid formsnon-covalent bonds with one or more atoms in the other amino acidthrough, for example, van der Waals, hydrophobic, or electrostaticforces. Basic amino acids include arginine, lysine, and histidine,whereas neutral hydrophilic amino acids include asparagine, glutamine,serine, and threonine. Hydrophobic amino acids include phenylalanine,tryptophan, tyrosine, alanine, isoleucine, leucine, and valine. Incertain embodiments, the amino acid at position 29 according to AHonumbering in the light chain variable region is lysine or arginine. Inone particular embodiment, the amino acid at position 29 according toAHo numbering in the light chain variable region is lysine. In relatedembodiments, the amino acid at position 61 according to AHo numbering inthe heavy chain variable region is isoleucine, leucine, valine,glutamine, asparagine, arginine, or lysine. In one embodiment, the aminoacid at position 61 according to AHo numbering in the heavy chainvariable region is isoleucine. In another embodiment, the amino acid atposition 61 according to AHo numbering in the heavy chain variableregion is glutamine or asparagine. In yet another embodiment, the aminoacid at position 61 according to AHo numbering in the heavy chainvariable region is arginine.

In some embodiments, the amino acid at position 66 according to AHonumbering in the heavy chain variable region of the antibody orantigen-binding fragment thereof is a basic or neutral hydrophilic aminoacid that interacts with amino acids Asn60 or Ile61 of human PAC1 (SEQID NO: 1). The amino acid at position 66 according AHo numbering in theheavy chain variable region may be glutamine, asparagine, arginine, orlysine. In one embodiment, the amino acid at position 66 according AHonumbering in the heavy chain variable region is arginine. In anotherembodiment, the amino acid at position 66 according AHo numbering in theheavy chain variable region is asparagine.

The paratope-epitope interactions described above were found tocorrelate with improvements in inhibitory potency with IC50 values inthe picomolar range. See Example 3. Thus, antibodies or antigen-bindingfragments thereof having the above-specified amino acids at positions 29in the light chain variable region and positions 61 and/or 66 in theheavy chain variable region according to AHo numbering and interactingwith the specified residues in the human PAC1 receptor (Glu120, Asp121,Asn60, and/or Ile61 of SEQ ID NO: 1) would be expected to have enhancedinhibitory potency, e.g. inhibit PACAP-induced activation of human PAC1with an IC50 less than 500 pM as measured by a cell-based cAMP assay. Insome embodiments, such antibodies or antigen-binding fragments mayinhibit PACAP-induced activation of human PAC1 with an IC50 less than300 pM as measured by a cell-based cAMP assay. In these and otherembodiments, the antibodies or antigen-binding fragments thereof mayhave a light chain variable region comprising a sequence that is atleast 90% identical to the sequence of SEQ ID NO: 52 and a heavy chainvariable region comprising a sequence that is at least 90% identical tothe sequence of SEQ ID NO: 191.

The antibodies or antigen-binding fragments of the invention maycomprise one or more complementarity determining regions (CDR) from thelight and heavy chain variable regions of antibodies that specificallybind to human PAC1 as described herein. The term “CDR” refers to thecomplementarity determining region (also termed “minimal recognitionunits” or “hypervariable region”) within antibody variable sequences.There are three heavy chain variable region CDRs (CDRH1, CDRH2 andCDRH3) and three light chain variable region CDRs (CDRL1, CDRL2 andCDRL3). The term “CDR region” as used herein refers to a group of threeCDRs that occur in a single variable region (i.e. the three light chainCDRs or the three heavy chain CDRs). The CDRs in each of the two chainstypically are aligned by the framework regions (FRs) to form a structurethat binds specifically with a specific epitope or domain on the targetprotein (e.g., human PAC1). From N-terminus to C-terminus,naturally-occurring light and heavy chain variable regions bothtypically conform with the following order of these elements: FR1, CDR1,FR2, CDR2, FR3, CDR3 and FR4. A numbering system has been devised forassigning numbers to amino acids that occupy positions in each of thesedomains. This numbering system is defined in Kabat Sequences of Proteinsof Immunological Interest (1987 and 1991, NIH, Bethesda, Md.), orChothia & Lesk, 1987, J. Mol. Biol. 196:901-917; Chothia et al., 1989,Nature 342:878-883. Complementarity determining regions (CDRs) andframework regions (FR) of a given antibody may be identified using thissystem. Other numbering systems for the amino acids in immunoglobulinchains include IMGT® (the international ImMunoGeneTics informationsystem; Lefranc et al., Dev. Comp. Immunol. 29:185-203; 2005) and AHo(Honegger and Pluckthun, J. Mol. Biol. 309(3):657-670; 2001).

In certain embodiments, the anti-PAC1 antibodies or antigen-bindingfragments thereof of the invention comprise at least one light chainvariable region comprising a CDRL1, CDRL2, and CDRL3, and at least oneheavy chain variable region comprising a CDRH1, CDRH2, and CDRH3 fromany of the anti-PAC1 antibodies described herein. Light chain and heavychain variable regions and associated CDRs of exemplary human anti-PAC1antibodies are set forth below in Tables 1A and 1B, respectively.

TABLE 1AExemplary Anti-Human PAC1 Antibody Light Chain Variable Region AminoAcid Sequences VL Ab ID. Group VL Amino Acid Sequence CDRL1 CDRL2 CDRL329G4 variants 29G4v10 LV-01 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIKR (SEQ ID NO: 52) 29G4v22 LV-02DIQLTQSPSFLSASVGDRVTITCRA RASQSIGRSLH YASQSLS HQSSRLPFT (SEQSQSIGRSLHWYQQKPGKAPKLLIK (SEQ ID NO: 6) (SEQ ID NO: 26) ID NO: 36)YASQSLSGVPSRFSGSGSGTEFTLT ISSLQPEDFATYYCHQSSRLPFTFG PGTKVDIKR(SEQ ID NO: 53) iPS: 420649 LV-03 EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLHYASQSLS HQSSRLPFT (SEQ SKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 54) iPS: 420653 LV-03EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLH YASQSLS HQSSRLPFT (SEQSKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 54) iPS: 420657 LV-03 EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLHYASQSLS HQSSRLPFT (SEQ SKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 54) iPS: 420661 LV-03EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLH YASQSLS HQSSRLPFT (SEQSKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 54) iPS: 420665 LV-03 EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLHYASQSLS HQSSRLPFT (SEQ SKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 54) iPS: 420672 LV-03EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLH YASQSLS HQSSRLPFT (SEQSKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 54) iPS: 420679 LV-03 EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLHYASQSLS HQSSRLPFT (SEQ SKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 54) iPS: 420686 LV-03EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLH YASQSLS HQSSRLPFT (SEQSKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 54) iPS: 420690 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 420697 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 420704 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 420711 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 420718 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 420725 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 420732 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 420739 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 420746 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 420753 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 420760 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 420767 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 420774 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 420781 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 420788 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 420795 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 420802 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 420809 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 420816 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 420823 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 420830 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 420837 LV-03EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLH YASQSLS HQSSRLPFT (SEQSKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 54) iPS: 420841 LV-03 EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLHYASQSLS HQSSRLPFT (SEQ SKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 54) iPS: 420845 LV-03EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLH YASQSLS HQSSRLPFT (SEQSKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 54) iPS: 420849 LV-03 EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLHYASQSLS HQSSRLPFT (SEQ SKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 54) iPS: 420853 LV-03EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLH YASQSLS HQSSRLPFT (SEQSKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 54) iPS: 420857 LV-03 EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLHYASQSLS HQSSRLPFT (SEQ SKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 54) iPS: 420861 LV-03EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLH YASQSLS HQSSRLPFT (SEQSKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 54) iPS: 420865 LV-03 EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLHYASQSLS HQSSRLPFT (SEQ SKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 54) iPS: 420869 LV-03EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLH YASQSLS HQSSRLPFT (SEQSKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 54) iPS: 420873 LV-03 EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLHYASQSLS HQSSRLPFT (SEQ SKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 54) iPS: 420877 LV-03EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLH YASQSLS HQSSRLPFT (SEQSKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 54) iPS: 420881 LV-03 EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLHYASQSLS HQSSRLPFT (SEQ SKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 54) iPS: 420885 LV-03EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLH YASQSLS HQSSRLPFT (SEQSKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 54) iPS: 420889 LV-03 EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLHYASQSLS HQSSRLPFT (SEQ SKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 54) iPS: 420893 LV-03EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLH YASQSLS HQSSRLPFT (SEQSKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 54) iPS: 420897 LV-03 EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLHYASQSLS HQSSRLPFT (SEQ SKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 54) iPS: 420901 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 420908 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 420915 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 420922 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 420929 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 420936 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 420943 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 420950 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 420957 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 420964 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 420971 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 420978 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 420985 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 420992 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 420999 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 421006 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 421013 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 421020 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 421027 LV-03EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLH YASQSLS HQSSRLPFT (SEQSKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 54) iPS: 421031 LV-03 EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLHYASQSLS HQSSRLPFT (SEQ SKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 54) iPS: 421035 LV-03EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLH YASQSLS HQSSRLPFT (SEQSKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 54) iPS: 421039 LV-03 EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLHYASQSLS HQSSRLPFT (SEQ SKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 54) iPS: 421043 LV-03EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLH YASQSLS HQSSRLPFT (SEQSKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 54) iPS: 421047 LV-03 EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLHYASQSLS HQSSRLPFT (SEQ SKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 54) iPS: 421051 LV-03EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLH YASQSLS HQSSRLPFT (SEQSKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 54) iPS: 421055 LV-03 EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLHYASQSLS HQSSRLPFT (SEQ SKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 54) iPS: 421059 LV-03EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLH YASQSLS HQSSRLPFT (SEQSKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 54) iPS: 421063 LV-03 EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLHYASQSLS HQSSRLPFT (SEQ SKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 54) iPS: 421067 LV-03EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLH YASQSLS HQSSRLPFT (SEQSKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 54) iPS: 421071 LV-03 EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLHYASQSLS HQSSRLPFT (SEQ SKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 54) iPS: 421075 LV-03EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLH YASQSLS HQSSRLPFT (SEQSKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 54) iPS: 421079 LV-03 EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLHYASQSLS HQSSRLPFT (SEQ SKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 54) iPS: 421083 LV-03EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLH YASQSLS HQSSRLPFT (SEQSKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 54) iPS: 421087 LV-03 EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLHYASQSLS HQSSRLPFT (SEQ SKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 54) iPS: 421091 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 421098 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 421105 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 421112 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 421119 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 421126 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 421133 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 421140 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 421147 LV-03EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLH YASQSLS HQSSRLPFT (SEQSKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 54) iPS: 421151 LV-05 EIVLTQSPATLSLSPGERATLSCRA RASQSVWRSLHYASQSLS HQSSRLPFT (SEQ SQSVWRSLHWYQQKPGQAPRLLI (SEQ ID NO: 8)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 56) iPS: 391478 LV-06EIVLTQSPATLSLSPGERATLSCRA RASQSVGRNLH YASQSLS HQSSRLPFT (SEQSQSVGRNLHWYQQKPGQAPRLLI (SEQ ID NO: 9) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 57) iPS: 421157 LV-07 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSMLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 37) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSMLPFTF GPGTKVDIK (SEQ ID NO: 58) iPS: 421163 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 391578 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 421170 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 421176 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 421182 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 421189 LV-08 EIVLTQSPATLSLSPGERATLSCRA RASKSVWRSLHYASQSLS HQSSRLPFT (SEQ SKSVWRSLHWYQQKPGQAPRLLI (SEQ ID NO: 10)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 59) iPS: 421195 LV-09EIVLTQSPATLSLSPGERATLSCRA RASKSVGRNLH YASQSLS HQSSRLPFT (SEQSKSVGRNLHWYQQKPGQAPRLLI (SEQ ID NO: 11) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 60) iPS: 421201 LV-10 EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLHYASQSLS HQSSMLPFT (SEQ SKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7)(SEQ ID NO: 26) ID NO: 37) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSMLPFTF GPGTKVDIK (SEQ ID NO: 61) iPS: 421207 LV-03EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLH YASQSLS HQSSRLPFT (SEQSKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 54) iPS: 421211 LV-03 EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLHYASQSLS HQSSRLPFT (SEQ SKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 54) iPS: 421215 LV-03EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLH YASQSLS HQSSRLPFT (SEQSKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 54) iPS: 421219 LV-03 EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLHYASQSLS HQSSRLPFT (SEQ SKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 54) iPS: 421223 LV-03EIVLTQSPATLSLSPGERATLSCRA RASKSVGRSLH YASQSLS HQSSRLPFT (SEQSKSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 7) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 54) iPS: 421227 LV-05 EIVLTQSPATLSLSPGERATLSCRA RASQSVWRSLHYASQSLS HQSSRLPFT (SEQ SQSVWRSLHWYQQKPGQAPRLLI (SEQ ID NO: 8)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 56) iPS: 421231 LV-06EIVLTQSPATLSLSPGERATLSCRA RASQSVGRNLH YASQSLS HQSSRLPFT (SEQSQSVGRNLHWYQQKPGQAPRLLI (SEQ ID NO: 9) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 57) iPS: 421235 LV-07 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSMLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 37) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSMLPFTF GPGTKVDIK (SEQ ID NO: 58) iPS: 421239 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 421246 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 421253 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 421260 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 421267 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 421274 LV-05 EIVLTQSPATLSLSPGERATLSCRA RASQSVWRSLHYASQSLS HQSSRLPFT (SEQ SQSVWRSLHWYQQKPGQAPRLLI (SEQ ID NO: 8)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 56) iPS: 421278 LV-06EIVLTQSPATLSLSPGERATLSCRA RASQSVGRNLH YASQSLS HQSSRLPFT (SEQSQSVGRNLHWYQQKPGQAPRLLI (SEQ ID NO: 9) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 57) iPS: 421282 LV-07 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSMLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 37) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSMLPFTF GPGTKVDIK (SEQ ID NO: 58) iPS: 421286 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 421293 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 421300 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 421307 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 421314 LV-05EIVLTQSPATLSLSPGERATLSCRA RASQSVWRSLH YASQSLS HQSSRLPFT (SEQSQSVWRSLHWYQQKPGQAPRLLI (SEQ ID NO: 8) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 56) iPS: 421318 LV-06 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRNLHYASQSLS HQSSRLPFT (SEQ SQSVGRNLHWYQQKPGQAPRLLI (SEQ ID NO: 9)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 57) iPS: 421322 LV-07EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSMLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 37)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSMLPFTF GPGTKVDIK(SEQ ID NO: 58) iPS: 421326 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 421333 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 421340 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 421347 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 421354 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 421361 LV-05EIVLTQSPATLSLSPGERATLSCRA RASQSVWRSLH YASQSLS HQSSRLPFT (SEQSQSVWRSLHWYQQKPGQAPRLLI (SEQ ID NO: 8) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 56) iPS: 421365 LV-06 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRNLHYASQSLS HQSSRLPFT (SEQ SQSVGRNLHWYQQKPGQAPRLLI (SEQ ID NO: 9)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 57) iPS: 421369 LV-07EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSMLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 37)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSMLPFTF GPGTKVDIK(SEQ ID NO: 58) iPS: 421373 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 421380 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 421387 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 421394 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 421855 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 421861 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 421867 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 421873 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 421879 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 421885 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 421891 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 421897 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 421903 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 421909 LV-04EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLH YASQSLS HQSSRLPFT (SEQSQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK(SEQ ID NO: 55) iPS: 421915 LV-04 EIVLTQSPATLSLSPGERATLSCRA RASQSVGRSLHYASQSLS HQSSRLPFT (SEQ SQSVGRSLHWYQQKPGQAPRLLI (SEQ ID NO: 5)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIK (SEQ ID NO: 55) iPS: 480711 LV-11EIVLTQSPATLSLSPGERATLSCRA RASKSVGWSLH YASQSLS HQSSRLPFT (SEQSKSVGWSLHWYQQKPGQAPRLLI (SEQ ID NO: 12) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIKR(SEQ ID NO: 62) iPS: 480706 LV-11 EIVLTQSPATLSLSPGERATLSCRA RASKSVGWSLHYASQSLS HQSSRLPFT (SEQ SKSVGWSLHWYQQKPGQAPRLLI (SEQ ID NO: 12)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIKR (SEQ ID NO: 62) iPS: 480713 LV-12EIVLTQSPATLSLSPGERATLSCRA RASKSVGYSLH YASQSLS HQSSRLPFT (SEQSKSVGYSLHWYQQKPGQAPRLLI (SEQ ID NO: 13) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIKR(SEQ ID NO: 63) iPS: 480705 LV-11 EIVLTQSPATLSLSPGERATLSCRA RASKSVGWSLHYASQSLS HQSSRLPFT (SEQ SKSVGWSLHWYQQKPGQAPRLLI (SEQ ID NO: 12)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIKR (SEQ ID NO: 62) iPS: 480707 LV-11EIVLTQSPATLSLSPGERATLSCRA RASKSVGWSLH YASQSLS HQSSRLPFT (SEQSKSVGWSLHWYQQKPGQAPRLLI (SEQ ID NO: 12) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIKR(SEQ ID NO: 62) iPS: 480708 LV-11 EIVLTQSPATLSLSPGERATLSCRA RASKSVGWSLHYASQSLS HQSSRLPFT (SEQ SKSVGWSLHWYQQKPGQAPRLLI (SEQ ID NO: 12)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIKR (SEQ ID NO: 62) iPS: 480709 LV-13EIVLTQSPATLSLSPGERATLSCRA RASKAVGWSLH YASQSLS HQSSRLPFT (SEQSKAVGWSLHWYQQKPGQAPRLLI (SEQ ID NO: 14) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIKR(SEQ ID NO: 64) iPS: 480712 LV-11 EIVLTQSPATLSLSPGERATLSCRA RASKSVGWSLHYASQSLS HQSSRLPFT (SEQ SKSVGWSLHWYQQKPGQAPRLLI (SEQ ID NO: 12)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIKR (SEQ ID NO: 62) iPS: 480704 LV-11EIVLTQSPATLSLSPGERATLSCRA RASKSVGWSLH YASQSLS HQSSRLPFT (SEQSKSVGWSLHWYQQKPGQAPRLLI (SEQ ID NO: 12) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIKR(SEQ ID NO: 62) iPS: 480710 LV-11 EIVLTQSPATLSLSPGERATLSCRA RASKSVGWSLHYASQSLS HQSSRLPFT (SEQ SKSVGWSLHWYQQKPGQAPRLLI (SEQ ID NO: 12)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIKR (SEQ ID NO: 62) iPS: 480716 LV-14EIVLTQSPATLSLSPGERATLSCRA RASKSVGQSLH YASQSLS HQSSRLPFT (SEQSKSVGQSLHWYQQKPGQAPRLLI (SEQ ID NO: 15) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIKR(SEQ ID NO: 65) iPS: 480715 LV-14 EIVLTQSPATLSLSPGERATLSCRA RASKSVGQSLHYASQSLS HQSSRLPFT (SEQ SKSVGQSLHWYQQKPGQAPRLLI (SEQ ID NO: 15)(SEQ ID NO: 26) ID NO: 36) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIKR (SEQ ID NO: 65) iPS: 480717 LV-14EIVLTQSPATLSLSPGERATLSCRA RASKSVGQSLH YASQSLS HQSSRLPFT (SEQSKSVGQSLHWYQQKPGQAPRLLI (SEQ ID NO: 15) (SEQ ID NO: 26) ID NO: 36)KYASQSLSGIPARFSGSGSGTDFTL TISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIKR(SEQ ID NO: 65) iPS: 480714 LV-15 EIVLTQSPATLSLSPGERATLSCRA RASRSVGLALHYASQSLS HQSSFLPFT (SEQ SRSVGLALHWYQQKPGQAPRLLI (SEQ ID NO: 16)(SEQ ID NO: 26) ID NO: 38) KYASQSLSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQSSRLPFTF GPGTKVDIKR (SEQ ID NO: 66) 19H8 variants 19H8LV-16 DIQMTQSPSSLSASVGDRITITCRA RASQSISRYLN AASSLQS QQSYSPPFT (SEQSQSISRYLNWYQQKPGKAPKLLIY (SEQ ID NO: 17) (SEQ ID NO: 27) ID NO: 39)AASSLQSGIPSRFSGSGSGTDFTLTI NSLQPEDFATYFCQQSYSPPFTFGP GTKVDIKR(SEQ ID NO: 67) iPS: 448202 LV-17 DIQMTQSPSSLSASVGDRITITCRA RASQSISRYLNAGQRLQS QQAIGMPYT SQSISRYLNWYQQKPGKAPKLLIF (SEQ ID NO: 17)(SEQ ID NO: 28) (SEQ ID NO: 40) AGQRLQSGIPSRFSGSGSGTDFTLTINSLQPEDFATYFCQQAIGMPYTF GPGTKVDIK (SEQ ID NO: 68) iPS: 449375 LV-18DIQMTQSPSSLSASVGDRITITCRA RASQYIVRYLN AAHHLQS QQAIQEPYT (SEQSQYIVRYLNWYQQKPGKAPKLLI (SEQ ID NO: 18) (SEQ ID NO: 29) ID NO: 41)YAAHHLQSGIPSRFSGSGSGTDFT LTINSLQPEDFATYFCQQAIQEPYT FGPGTKVDIK(SEQ ID NO: 69) iPS: 448083 LV-19 DIQMTQSPSSLSASVGDRITITCRA RASQTIVRYLNAGQRLQS QQAIINPYT (SEQ SQTIVRYLNWYQQKPGKAPKLLIF (SEQ ID NO: 19)(SEQ ID NO: 28) ID NO: 42) AGQRLQSGIPSRFSGSGSGTDFTLTINSLQPEDFATYFCQQAIINPYTFG PGTKVDIK (SEQ ID NO: 70) iPS: 452128 LV-20DIQMTQSPSSLSASVGDRITITCRA RASQYIVRYLN AANMLQS QQAINQPYTSQYIVRYLNWYQQKPGKAPKLLI (SEQ ID NO: 18) (SEQ ID NO: 30) (SEQ ID NO: 43)YAANMLQSGIPSRFSGSGSGTDFT LTINSLQPEDFATYFCQQAINQPYT FGPGTKVDIK(SEQ ID NO: 71) iPS: 448195 LV-21 DIQMTQSPSSLSASVGDRITITCRA RASQKIARYLVAANMLQS QQSIQQPYT (SEQ SQKIARYLVWYQQKPGKAPKLLI (SEQ ID NO: 20)(SEQ ID NO: 30) ID NO: 44) YAANMLQSGIPSRFSGSGSGTDFTLTINSLQPEDFATYFCQQSIQQPYT FGPGTKVDIK (SEQ ID NO: 72) iPS: 448466 LV-22DIQMTQSPSSLSASVGDRITITCRA RASQSISRYLN AGQRLQS QQAIQQPYTSQSISRYLNWYQQKPGKAPKLLIF (SEQ ID NO: 17) (SEQ ID NO: 28) (SEQ ID NO: 45)AGQRLQSGIPSRFSGSGSGTDFTLT INSLQPEDFATYFCQQAIQQPYTFG PGTKVDIKR(SEQ ID NO: 73) iPS: 448689 LV-23 DIQMTQSPSSLSASVGDRITITCRA RASQYIVRYLNASYNLQS QQAIMAPYT SQYIVRYLNWYQQKPGKAPKLLI (SEQ ID NO: 18)(SEQ ID NO: 31) (SEQ ID NO: 46) YASYNLQSGIPSRFSGSGSGTDFTLTINSLQPEDFATYFCQQAIMAPYT FGPGTKVDIK (SEQ ID NO: 74) iPS: 449034 LV-24DIQMTQSPSSLSASVGDRITITCRA RASQPIAQYLN AGRYLQS QQAIQNPYTSQPIAQYLNWYQQKPGKAPKLLIY (SEQ ID NO: 21) (SEQ ID NO: 32) (SEQ ID NO: 47)AGRYLQSGIPSRFSGSGSGTDFTLT INSLQPEDFATYFCQQAIQNPYTFG PGTKVDIK(SEQ ID NO: 75) iPS: 448075 LV-25 DIQMTQSPSSLSASVGDRITITCRA RASQSISRYLNAGQRLQS QQAIVQPYT SQSISRYLNWYQQKPGKAPKLLIF (SEQ ID NO: 17)(SEQ ID NO: 28) (SEQ ID NO: 48) AGQRLQSGIPSRFSGSGSGTDFTLTINSLQPEDFATYFCQQAIVQPYTFG PGTKVDIK (SEQ ID NO: 76) iPS: 448924 LV-26DIQMTQSPSSLSASVGDRITITCRA RASQPISRYLS AGQRLQS QQAISIPYT (SEQSQPISRYLSWYQQKPGKAPKLLIF (SEQ ID NO: 22) (SEQ ID NO: 28) ID NO: 49)AGQRLQSGIPSRFSGSGSGTDFTLT INSLQPEDFATYFCQQAISIPYTFGP GTKVDIK(SEQ ID NO: 77) iPS: 448752 LV-27 DIQMTQSPSSLSASVGDRITITCRA RASQQIARYLNASYNLQS QQAIIQPYT (SEQ SQQIARYLNWYQQKPGKAPKLLI (SEQ ID NO: 23)(SEQ ID NO: 31) ID NO: 50) YASYNLQSGIPSRFSGSGSGTDFTLTINSLQPEDFATYFCQQAIIQPYTF GPGTKVDIK (SEQ ID NO: 78) iPS: 448772 LV-28DIQMTQSPSSLSASVGDRITITCRA RASQSISRYLN ASYNLQS QQAIQNPYTSQSISRYLNWYQQKPGKAPKLLIY (SEQ ID NO: 17) (SEQ ID NO: 31) (SEQ ID NO: 47)ASYNLQSGIPSRFSGSGSGTDFTLT INSLQPEDFATYFCQQAIQNPYTFG PGTKVDIK(SEQ ID NO: 79) iPS: 448117 LV-29 DIQMTQSPSSLSASVGDRITITCRA RASQTIVRYLNAGQRLQS QQSIQTPYT (SEQ SQTIVRYLNWYQQKPGKAPKLLIF (SEQ ID NO: 19)(SEQ ID NO: 28) ID NO: 51) AGQRLQSGIPSRFSGSGSGTDFTLTINSLQPEDFATYFCQQSIQTPYTFG PGTKVDIK (SEQ ID NO: 80) iPS: 448788 LV-30DIQMTQSPSSLSASVGDRITITCRA RASQSISRYLN AGRILQS QQAIINPYT (SEQSQSISRYLNWYQQKPGKAPKLLIY (SEQ ID NO: 17) (SEQ ID NO: 33) ID NO: 42)AGRILQSGIPSRFSGSGSGTDFTLTI NSLQPEDFATYFCQQAIINPYTFGP GTKVDIK(SEQ ID NO: 81) iPS: 448593 LV-28 DIQMTQSPSSLSASVGDRITITCRA RASQSISRYLNASYNLQS QQAIQNPYT SQSISRYLNWYQQKPGKAPKLLIY (SEQ ID NO: 17)(SEQ ID NO: 31) (SEQ ID NO: 47) ASYNLQSGIPSRFSGSGSGTDFTLTINSLQPEDFATYFCQQAIQNPYTFG PGTKVDIK (SEQ ID NO: 79) iPS: 448238 LV-31DIQMTQSPSSLSASVGDRITITCRA RASQRIARYLN AGSILQS QQAIQNPYTSQRIARYLNWYQQKPGKAPKLLIF (SEQ ID NO: 24) (SEQ ID NO: 34) (SEQ ID NO: 47)AGSILQSGIPSRFSGSGSGTDFTLTI NSLQPEDFATYFCQQAIQNPYTFG PGTKVDIK(SEQ ID NO: 82) iPS: 448901 LV-32 DIQMTQSPSSLSASVGDRITITCRA RASQSISRYLNASYNLQS QQSIQQPYT (SEQ SQSISRYLNWYQQKPGKAPKLLIY (SEQ ID NO: 17)(SEQ ID NO: 31) ID NO: 44) ASYNLQSGIPSRFSGSGSGTDFTLTINSLQPEDFATYFCQQSIQQPYTFG PGTKVDIK (SEQ ID NO: 83) iPS: 448655 LV-33DIQMTQSPSSLSASVGDRITITCRA RASQYIVRYLN ASYNLQS QQAIQQPYTSQYIVRYLNWYQQKPGKAPKLLI (SEQ ID NO: 18) (SEQ ID NO: 31) (SEQ ID NO: 45)YASYNLQSGIPSRFSGSGSGTDFTL TINSLQPEDFATYFCQQAIQQPYTF GPGTKVDIK(SEQ ID NO: 84) iPS: 448730 LV-34 DIQMTQSPSSLSASVGDRITITCRA RASQMIARYLNASYNLQS QQAIINPYT (SEQ SQMIARYLNWYQQKPGKAPKLLI (SEQ ID NO: 25)(SEQ ID NO: 31) ID NO: 42) YASYNLQSGIPSRFSGSGSGTDFTLTINSLQPEDFATYFCQQAIINPYTF GPGTKVDIK (SEQ ID NO: 85) iPS: 449027 LV-35DIQMTQSPSSLSASVGDRITITCRA RASQYIVRYLN GARNLQS QQSIQTPYT (SEQSQYIVRYLNWYQQKPGKAPKLLI (SEQ ID NO: 18) (SEQ ID NO: 35) ID NO: 51)YGARNLQSGIPSRFSGSGSGTDFTL TINSLQPEDFATYFCQQSIQTPYTF GPGTKVDIK(SEQ ID NO: 86) 3574 LV-36 DIQMTQSPSSLSASVGDRITITCRA RASQSISRYLN AASSLQSQQSYSPPFT (SEQ SQSISRYLNWYQQKPGKAPKLLIY (SEQ ID NO: 17) (SEQ ID NO: 27)ID NO: 39) AASSLQSGIPSRFSGSGSGTDFTLTI NSLQPEDFATYFCQQSYSPPFTFGP GTKVDIK(SEQ ID NO: 87) 3575 LV-27 DIQMTQSPSSLSASVGDRITITCRA RASQQIARYLN ASYNLQSQQAIIQPYT (SEQ SQQIARYLNWYQQKPGKAPKLLI (SEQ ID NO: 23) (SEQ ID NO: 31)ID NO: 50) YASYNLQSGIPSRFSGSGSGTDFTL TINSLQPEDFATYFCQQAIIQPYTF GPGTKVDIK(SEQ ID NO: 78)

TABLE 1BExemplary Anti-Human PAC1 Antibody Heavy Chain Variable Region AminoAcid Sequences VH Ab ID. Group VH Amino Acid Sequence CDRH1 CDRH2 CDRH329G4 variants 29G4v10 HV-01 QVQLVESGGGVVQPGRSLR RFAMH VISYDGGNKYYAESVKGGYDVLTGYPDY LSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 106)(SEQ ID NO: 171) QAPGKGLEWVAVISYDGGN NO: 88) KYYAESVKGRFTISRDNSKNTLYLQMNSLRAEDTALFYC ARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 191) 29G4v22HV-02 QVQLVESGAEVVKPGASVK RFAMH VISYDGGNKYYAESVKG GYDVLTGYPDYVSCKASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 106) (SEQ ID NO: 171)QAPGQGLEWMGVISYDGGN NO: 88) KYYAESVKGRVTMTRDTST STLYMELSSLRSEDTAVYYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 192) iPS: 420649 HV-03QVQLVESGGGVVQPGRSLR RFAMH VISYNGGNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 107) (SEQ ID NO: 171)QAPGKGLEWVAVISYNGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 193) iPS: 420653 HV-04QVQLVESGGGVVQPGRSLR RFAMH VISYIGGNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 108) (SEQ ID NO: 171)QAPGKGLEWVAVISYIGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 194) iPS: 420657 HV-05QVQLVESGGGVVQPGRSLR RFAMH VISYQGGNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 109) (SEQ ID NO: 171)QAPGKGLEWVAVISYQGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 195) iPS: 420661 HV-06QVQLVESGGGVVQPGRSLR RFAMH VISYYGGNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 110) (SEQ ID NO: 171)QAPGKGLEWVAVISYYGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 196) iPS: 420665 HV-07QVQLVESGGGVVQPGRSLR RFAMH VISYDGRNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 111) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGRN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 197) iPS: 420672 HV-08QVQLVESGGGVVQPGRSLR RFAMH VISYDGNNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 112) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGNN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 198) iPS: 420679 HV-09QVQLVESGGGVVQPGRSLR RFAMH VISYDGGNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 113) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGGN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 199) iPS: 420686 HV-10QVQLVESGGGVVQPGRSLR RFAMH VISYDGGNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 106) (SEQ ID NO: 172)QAPGKGLEWVAVISYDGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 200) iPS: 420690 HV-11QVQLVESGGGVVQPGRSLR RFAMH VISYNGRNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 114) (SEQ ID NO: 171)QAPGKGLEWVAVISYNGRN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 201) iPS: 420697 HV-12QVQLVESGGGVVQPGRSLR RFAMH VISYIGRNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 115) (SEQ ID NO: 171)QAPGKGLEWVAVISYIGRNK NO: 88) YYAESVKGRFTISRDNSKNT LYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTLV TVSS (SEQ ID NO: 202) iPS: 420704 HV-13QVQLVESGGGVVQPGRSLR RFAMH VISYQGRNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 116) (SEQ ID NO: 171)QAPGKGLEWVAVISYQGRN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 203) iPS: 420711 HV-14QVQLVESGGGVVQPGRSLR RFAMH VISYYGRNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 117) (SEQ ID NO: 171)QAPGKGLEWVAVISYYGRN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 204) iPS: 420718 HV-15QVQLVESGGGVVQPGRSLR RFAMH VISYNGNNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 118) (SEQ ID NO: 171)QAPGKGLEWVAVISYNGNN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 205) iPS: 420725 HV-16QVQLVESGGGVVQPGRSLR RFAMH VISYIGNNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 119) (SEQ ID NO: 171)QAPGKGLEWVAVISYIGNN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 206) iPS: 420732 HV-17QVQLVESGGGVVQPGRSLR RFAMH VISYQGNNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 120) (SEQ ID NO: 171)QAPGKGLEWVAVISYQGNN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 207) iPS: 420739 HV-18QVQLVESGGGVVQPGRSLR RFAMH VISYYGNNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 121) (SEQ ID NO: 171)QAPGKGLEWVAVISYYGNN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 208) iPS: 420746 HV-19QVQLVESGGGVVQPGRSLR RFAMH VISYNGGNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 122) (SEQ ID NO: 171)QAPGKGLEWVAVISYNGGN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 209) iPS: 420753 HV-20QVQLVESGGGVVQPGRSLR RFAMH VISYIGGNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 123) (SEQ ID NO: 171)QAPGKGLEWVAVISYIGGN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 210) iPS: 420760 HV-21QVQLVESGGGVVQPGRSLR RFAMH VISYQGGNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 124) (SEQ ID NO: 171)QAPGKGLEWVAVISYQGGN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 211) iPS: 420767 HV-22QVQLVESGGGVVQPGRSLR RFAMH VISYYGGNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 125) (SEQ ID NO: 171)QAPGKGLEWVAVISYYGGN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 212) iPS: 420774 HV-23QVQLVESGGGVVQPGRSLR RFAMH VISYNGGNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 107) (SEQ ID NO: 172)QAPGKGLEWVAVISYNGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 213) iPS: 420781 HV-24QVQLVESGGGVVQPGRSLR RFAMH VISYIGGNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 108) (SEQ ID NO: 172)QAPGKGLEWVAVISYIGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 214) iPS: 420788 HV-25QVQLVESGGGVVQPGRSLR RFAMH VISYQGGNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 109) (SEQ ID NO: 172)QAPGKGLEWVAVISYQGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 215) iPS: 420795 HV-26QVQLVESGGGVVQPGRSLR RFAMH VISYYGGNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 110) (SEQ ID NO: 172)QAPGKGLEWVAVISYYGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 216) iPS: 420802 HV-27QVQLVESGGGVVQPGRSLR RFAMH VISYDGRNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 126) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGRN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 217) iPS: 420809 HV-28QVQLVESGGGVVQPGRSLR RFAMH VISYDGNNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 127) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGNN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 218) iPS: 420816 HV-29QVQLVESGGGVVQPGRSLR RFAMH VISYDGRNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 111) (SEQ ID NO: 172)QAPGKGLEWVAVISYDGRN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 219) iPS: 420823 HV-30QVQLVESGGGVVQPGRSLR RFAMH VISYDGNNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 112) (SEQ ID NO: 172)QAPGKGLEWVAVISYDGNN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 220) iPS: 420830 HV-31QVQLVESGGGVVQPGRSLR RFAMH VISYDGGNKYYARSVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 113) (SEQ ID NO: 172)QAPGKGLEWVAVISYDGGN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 221) iPS: 420837 HV-11QVQLVESGGGVVQPGRSLR RFAMH VISYNGRNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 114) (SEQ ID NO: 171)QAPGKGLEWVAVISYNGRN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 201) iPS: 420841 HV-12QVQLVESGGGVVQPGRSLR RFAMH VISYIGRNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 115) (SEQ ID NO: 171)QAPGKGLEWVAVISYIGRNK NO: 88) YYAESVKGRFTISRDNSKNT LYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTLV TVSS (SEQ ID NO: 202) iPS: 420845 HV-13QVQLVESGGGVVQPGRSLR RFAMH VISYQGRNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 116) (SEQ ID NO: 171)QAPGKGLEWVAVISYQGRN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 203) iPS: 420849 HV-14QVQLVESGGGVVQPGRSLR RFAMH VISYYGRNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 117) (SEQ ID NO: 171)QAPGKGLEWVAVISYYGRN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 204) iPS: 420853 HV-15QVQLVESGGGVVQPGRSLR RFAMH VISYNGNNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 118) (SEQ ID NO: 171)QAPGKGLEWVAVISYNGNN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 205) iPS: 420857 HV-16QVQLVESGGGVVQPGRSLR RFAMH VISYIGNNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 119) (SEQ ID NO: 171)QAPGKGLEWVAVISYIGNN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 206) iPS: 420861 HV-17QVQLVESGGGVVQPGRSLR RFAMH VISYQGNNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 120) (SEQ ID NO: 171)QAPGKGLEWVAVISYQGNN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 207) iPS: 420865 HV-18QVQLVESGGGVVQPGRSLR RFAMH VISYYGNNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 121) (SEQ ID NO: 171)QAPGKGLEWVAVISYYGNN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 208) iPS: 420869 HV-19QVQLVESGGGVVQPGRSLR RFAMH VISYNGGNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 122) (SEQ ID NO: 171)QAPGKGLEWVAVISYNGGN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 209) iPS: 420873 HV-20QVQLVESGGGVVQPGRSLR RFAMH VISYIGGNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 123) (SEQ ID NO: 171)QAPGKGLEWVAVISYIGGN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 210) iPS: 420877 HV-21QVQLVESGGGVVQPGRSLR RFAMH VISYQGGNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 124) (SEQ ID NO: 171)QAPGKGLEWVAVISYQGGN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 211) iPS: 420881 HV-22QVQLVESGGGVVQPGRSLR RFAMH VISYYGGNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 125) (SEQ ID NO: 171)QAPGKGLEWVAVISYYGGN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 212) iPS: 420885 HV-23QVQLVESGGGVVQPGRSLR RFAMH VISYNGGNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 107) (SEQ ID NO: 172)QAPGKGLEWVAVISYNGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 213) iPS: 420889 HV-24QVQLVESGGGVVQPGRSLR RFAMH VISYIGGNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 108) (SEQ ID NO: 172)QAPGKGLEWVAVISYIGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 214) iPS: 420893 HV-25QVQLVESGGGVVQPGRSLR RFAMH VISYQGGNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 109) (SEQ ID NO: 172)QAPGKGLEWVAVISYQGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 215) iPS: 420897 HV-26QVQLVESGGGVVQPGRSLR RFAMH VISYYGGNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 110) (SEQ ID NO: 172)QAPGKGLEWVAVISYYGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 216) iPS: 420901 HV-32QVQLVESGGGVVQPGRSLR RFAMH VISYNGRNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 128) (SEQ ID NO: 171)QAPGKGLEWVAVISYNGRN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 222) iPS: 420908 HV-33QVQLVESGGGVVQPGRSLR RFAMH VISYIGRNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 129) (SEQ ID NO: 171)QAPGKGLEWVAVISYIGRNK NO: 88) YYARSVKGRFTISRDNSKNT LYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTLV TVSS (SEQ ID NO: 223) iPS: 420915 HV-34QVQLVESGGGVVQPGRSLR RFAMH VISYQGRNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 130) (SEQ ID NO: 171)QAPGKGLEWVAVISYQGRN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 224) iPS: 420922 HV-35QVQLVESGGGVVQPGRSLR RFAMH VISYYGRNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 131) (SEQ ID NO: 171)QAPGKGLEWVAVISYYGRN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 225) iPS: 420929 HV-36QVQLVESGGGVVQPGRSLR RFAMH VISYNGNNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 132) (SEQ ID NO: 171)QAPGKGLEWVAVISYNGNN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 226) iPS: 420936 HV-37QVQLVESGGGVVQPGRSLR RFAMH VISYIGNNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 133) (SEQ ID NO: 171)QAPGKGLEWVAVISYIGNN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 227) iPS: 420943 HV-38QVQLVESGGGVVQPGRSLR RFAMH VISYQGNNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 134) (SEQ ID NO: 171)QAPGKGLEWVAVISYQGNN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 228) iPS: 420950 HV-39QVQLVESGGGVVQPGRSLR RFAMH VISYYGNNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 135) (SEQ ID NO: 171)QAPGKGLEWVAVISYYGNN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 229) iPS: 420957 HV-40QVQLVESGGGVVQPGRSLR RFAMH VISYNGRNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 114) (SEQ ID NO: 172)QAPGKGLEWVAVISYNGRN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 230) iPS: 420964 HV-41QVQLVESGGGVVQPGRSLR RFAMH VISYIGRNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 115) (SEQ ID NO: 172)QAPGKGLEWVAVISYIGRNK NO: 88) YYAESVKGRFTISRDNSKNT LYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTLV TVSS (SEQ ID NO: 231) iPS: 420971 HV-42QVQLVESGGGVVQPGRSLR RFAMH VISYQGRNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 116) (SEQ ID NO: 172)QAPGKGLEWVAVISYQGRN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 232) iPS: 420978 HV-43QVQLVESGGGVVQPGRSLR RFAMH VISYYGRNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 117) (SEQ ID NO: 172)QAPGKGLEWVAVISYYGRN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 233) iPS: 420985 HV-44QVQLVESGGGVVQPGRSLR RFAMH VISYNGNNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 118) (SEQ ID NO: 172)QAPGKGLEWVAVISYNGNN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 234) iPS: 420992 HV-45QVQLVESGGGVVQPGRSLR RFAMH VISYIGNNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 119) (SEQ ID NO: 172)QAPGKGLEWVAVISYIGNN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 235) iPS: 420999 HV-46QVQLVESGGGVVQPGRSLR RFAMH VISYQGNNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 120) (SEQ ID NO: 172)QAPGKGLEWVAVISYQGNN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 236) iPS: 421006 HV-47QVQLVESGGGVVQPGRSLR RFAMH VISYYGNNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 121) (SEQ ID NO: 172)QAPGKGLEWVAVISYYGNN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 237) iPS: 421013 HV-48QVQLVESGGGVVQPGRSLR RFAMH VISYDGRNKYYARSVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 126) (SEQ ID NO: 172)QAPGKGLEWVAVISYDGRN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 238) iPS: 421020 HV-49QVQLVESGGGVVQPGRSLR RFAMH VISYDGNNKYYARSVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 127) (SEQ ID NO: 172)QAPGKGLEWVAVISYDGNN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 239) iPS: 421027 HV-32QVQLVESGGGVVQPGRSLR RFAMH VISYNGRNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 128) (SEQ ID NO: 171)QAPGKGLEWVAVISYNGRN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 222) iPS: 421031 HV-33QVQLVESGGGVVQPGRSLR RFAMH VISYIGRNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 129) (SEQ ID NO: 171)QAPGKGLEWVAVISYIGRNK NO: 88) YYARSVKGRFTISRDNSKNT LYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTLV TVSS (SEQ ID NO: 223) iPS: 421035 HV-34QVQLVESGGGVVQPGRSLR RFAMH VISYQGRNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 130) (SEQ ID NO: 171)QAPGKGLEWVAVISYQGRN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 224) iPS: 421039 HV-35QVQLVESGGGVVQPGRSLR RFAMH VISYYGRNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 131) (SEQ ID NO: 171)QAPGKGLEWVAVISYYGRN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 225) iPS: 421043 HV-36QVQLVESGGGVVQPGRSLR RFAMH VISYNGNNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 132) (SEQ ID NO: 171)QAPGKGLEWVAVISYNGNN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 226) iPS: 421047 HV-37QVQLVESGGGVVQPGRSLR RFAMH VISYIGNNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 133) (SEQ ID NO: 171)QAPGKGLEWVAVISYIGNN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 227) iPS: 421051 HV-38QVQLVESGGGVVQPGRSLR RFAMH VISYQGNNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 134) (SEQ ID NO: 171)QAPGKGLEWVAVISYQGNN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 228) iPS: 421055 HV-39QVQLVESGGGVVQPGRSLR RFAMH VISYYGNNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 135) (SEQ ID NO: 171)QAPGKGLEWVAVISYYGNN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 229) iPS: 421059 HV-40QVQLVESGGGVVQPGRSLR RFAMH VISYNGRNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 114) (SEQ ID NO: 172)QAPGKGLEWVAVISYNGRN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 230) iPS: 421063 HV-41QVQLVESGGGVVQPGRSLR RFAMH VISYIGRNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 115) (SEQ ID NO: 172)QAPGKGLEWVAVISYIGRNK NO: 88) YYAESVKGRFTISRDNSKNT LYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTLV TVSS (SEQ ID NO: 231) iPS: 421067 HV-42QVQLVESGGGVVQPGRSLR RFAMH VISYQGRNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 116) (SEQ ID NO: 172)QAPGKGLEWVAVISYQGRN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 232) iPS: 421071 HV-43QVQLVESGGGVVQPGRSLR RFAMH VISYYGRNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 117) (SEQ ID NO: 172)QAPGKGLEWVAVISYYGRN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 233) iPS: 421075 HV-44QVQLVESGGGVVQPGRSLR RFAMH VISYNGNNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 118) (SEQ ID NO: 172)QAPGKGLEWVAVISYNGNN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 234) iPS: 421079 HV-45QVQLVESGGGVVQPGRSLR RFAMH VISYIGNNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 119) (SEQ ID NO: 172)QAPGKGLEWVAVISYIGNN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 235) iPS: 421083 HV-46QVQLVESGGGVVQPGRSLR RFAMH VISYQGNNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 120) (SEQ ID NO: 172)QAPGKGLEWVAVISYQGNN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 236) iPS: 421087 HV-47QVQLVESGGGVVQPGRSLR RFAMH VISYYGNNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 121) (SEQ ID NO: 172)QAPGKGLEWVAVISYYGNN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 237) iPS: 421091 HV-50QVQLVESGGGVVQPGRSLR RFAMH VISYNGRNKYYARSVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 128) (SEQ ID NO: 172)QAPGKGLEWVAVISYNGRN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 240) iPS: 421098 HV-51QVQLVESGGGVVQPGRSLR RFAMH VISYIGRNKYYARSVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 129) (SEQ ID NO: 172)QAPGKGLEWVAVISYIGRNK NO: 88) YYARSVKGRFTISRDNSKNT LYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTLV TVSS (SEQ ID NO: 241) iPS: 421105 HV-52QVQLVESGGGVVQPGRSLR RFAMH VISYQGRNKYYARSVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 130) (SEQ ID NO: 172)QAPGKGLEWVAVISYQGRN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 242) iPS: 421112 HV-53QVQLVESGGGVVQPGRSLR RFAMH VISYYGRNKYYARSVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 131) (SEQ ID NO: 172)QAPGKGLEWVAVISYYGRN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 243) iPS: 421119 HV-54QVQLVESGGGVVQPGRSLR RFAMH VISYNGNNKYYARSVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 132) (SEQ ID NO: 172)QAPGKGLEWVAVISYNGNN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 244) iPS: 421126 HV-55QVQLVESGGGVVQPGRSLR RFAMH VISYIGNNKYYARSVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 133) (SEQ ID NO: 172)QAPGKGLEWVAVISYIGNN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 245) iPS: 421133 HV-56QVQLVESGGGVVQPGRSLR RFAMH VISYQGNNKYYARSVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 134) (SEQ ID NO: 172)QAPGKGLEWVAVISYQGNN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 246) iPS: 421140 HV-57QVQLVESGGGVVQPGRSLR RFAMH VISYYGNNKYYARSVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 135) (SEQ ID NO: 172)QAPGKGLEWVAVISYYGNN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 247) iPS: 421147 HV-57QVQLVESGGGVVQPGRSLR RFAMH VISYYGNNKYYARSVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 135) (SEQ ID NO: 172)QAPGKGLEWVAVISYYGNN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 247) iPS: 421151 HV-01QVQLVESGGGVVQPGRSLR RFAMH VISYDGGNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 106) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 191) iPS: 391478 HV-01QVQLVESGGGVVQPGRSLR RFAMH VISYDGGNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 106) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 191) iPS: 421157 HV-01QVQLVESGGGVVQPGRSLR RFAMH VISYDGGNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 106) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 191) iPS: 421163 HV-58QVQLVESGGGVVQPGRSLR HFAMH VISYDGGNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSHFAMHWVR (SEQ ID (SEQ ID NO: 106) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGGN NO: 89) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 248) iPS: 391578 HV-59QVQLVESGGGVVQPGRSLR RYAMH VISYDGGNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRYAMHWVR (SEQ ID (SEQ ID NO: 106) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGGN NO: 90) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 249) iPS: 421170 HV-60QVQLVESGGGVVQPGRSLR RFAMH VISFDGGNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 136) (SEQ ID NO: 171)QAPGKGLEWVAVISFDGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 250) iPS: 421176 HV-61QVQLVESGGGVVQPGRSLR RFAMH VISYDGANKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 137) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGAN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 251) iPS: 421182 HV-62QVQLVESGGGVVQPGRSLR RFAMH VISYDGGNKYYAESVKG GYDFLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 106) (SEQ ID NO: 173)QAPGKGLEWVAVISYDGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDFLTGYPDYWGQGTL VTVSS (SEQ ID NO: 252) iPS: 421189 HV-01QVQLVESGGGVVQPGRSLR RFAMH VISYDGGNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 106) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 191) iPS: 421195 HV-01QVQLVESGGGVVQPGRSLR RFAMH VISYDGGNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 106) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 191) iPS: 421201 HV-01QVQLVESGGGVVQPGRSLR RFAMH VISYDGGNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 106) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 191) iPS: 421207 HV-58QVQLVESGGGVVQPGRSLR HFAMH VISYDGGNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSHFAMHWVR (SEQ ID (SEQ ID NO: 106) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGGN NO: 89) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 248) iPS: 421211 HV-59QVQLVESGGGVVQPGRSLR RYAMH VISYDGGNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRYAMHWVR (SEQ ID (SEQ ID NO: 106) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGGN NO: 90) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 249) iPS: 421215 HV-60QVQLVESGGGVVQPGRSLR RFAMH VISFDGGNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 136) (SEQ ID NO: 171)QAPGKGLEWVAVISFDGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 250) iPS: 421219 HV-61QVQLVESGGGVVQPGRSLR RFAMH VISYDGANKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 137) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGAN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 251) iPS: 421223 HV-62QVQLVESGGGVVQPGRSLR RFAMH VISYDGGNKYYAESVKG GYDFLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 106) (SEQ ID NO: 173)QAPGKGLEWVAVISYDGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDFLTGYPDYWGQGTL VTVSS (SEQ ID NO: 252) iPS: 421227 HV-03QVQLVESGGGVVQPGRSLR RFAMH VISYNGGNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 107) (SEQ ID NO: 171)QAPGKGLEWVAVISYNGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 193) iPS: 421231 HV-03QVQLVESGGGVVQPGRSLR RFAMH VISYNGGNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 107) (SEQ ID NO: 171)QAPGKGLEWVAVISYNGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 193) iPS: 421235 HV-03QVQLVESGGGVVQPGRSLR RFAMH VISYNGGNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 107) (SEQ ID NO: 171)QAPGKGLEWVAVISYNGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 193) iPS: 421239 HV-63QVQLVESGGGVVQPGRSLR HFAMH VISYNGGNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSHFAMHWVR (SEQ ID (SEQ ID NO: 107) (SEQ ID NO: 171)QAPGKGLEWVAVISYNGGN NO: 89) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 253) iPS: 421246 HV-64QVQLVESGGGVVQPGRSLR RYAMH VISYNGGNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRYAMHWVR (SEQ ID (SEQ ID NO: 107) (SEQ ID NO: 171)QAPGKGLEWVAVISYNGGN NO: 90) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 254) iPS: 421253 HV-65QVQLVESGGGVVQPGRSLR RFAMH VISFNGGNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 138) (SEQ ID NO: 171)QAPGKGLEWVAVISFNGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 255) iPS: 421260 HV-66QVQLVESGGGVVQPGRSLR RFAMH VISYNGANKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 139) (SEQ ID NO: 171)QAPGKGLEWVAVISYNGAN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 256) iPS: 421267 HV-67QVQLVESGGGVVQPGRSLR RFAMH VISYNGGNKYYAESVKG GYDFLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 107) (SEQ ID NO: 173)QAPGKGLEWVAVISYNGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDFLTGYPDYWGQGTL VTVSS (SEQ ID NO: 257) iPS: 421274 HV-07QVQLVESGGGVVQPGRSLR RFAMH VISYDGRNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 111) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGRN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 197) iPS: 421278 HV-07QVQLVESGGGVVQPGRSLR RFAMH VISYDGRNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 111) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGRN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 197) iPS: 421282 HV-07QVQLVESGGGVVQPGRSLR RFAMH VISYDGRNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 111) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGRN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 197) iPS: 421286 HV-68QVQLVESGGGVVQPGRSLR HFAMH VISYDGRNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSHFAMHWVR (SEQ ID (SEQ ID NO: 111) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGRN NO: 89) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 258) iPS: 421293 HV-69QVQLVESGGGVVQPGRSLR RYAMH VISYDGRNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRYAMHWVR (SEQ ID (SEQ ID NO: 111) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGRN NO: 90) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 259) iPS: 421300 HV-70QVQLVESGGGVVQPGRSLR RFAMH VISFDGRNKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 140) (SEQ ID NO: 171)QAPGKGLEWVAVISFDGRN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 260) iPS: 421307 HV-71QVQLVESGGGVVQPGRSLR RFAMH VISYDGRNKYYAESVKG GYDFLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 111) (SEQ ID NO: 173)QAPGKGLEWVAVISYDGRN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDFLTGYPDYWGQGTL VTVSS (SEQ ID NO: 261) iPS: 421314 HV-09QVQLVESGGGVVQPGRSLR RFAMH VISYDGGNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 113) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGGN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 199) iPS: 421318 HV-09QVQLVESGGGVVQPGRSLR RFAMH VISYDGGNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 113) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGGN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 199) iPS: 421322 HV-09QVQLVESGGGVVQPGRSLR RFAMH VISYDGGNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 113) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGGN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 199) iPS: 421326 HV-72QVQLVESGGGVVQPGRSLR HFAMH VISYDGGNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSHFAMHWVR (SEQ ID (SEQ ID NO: 113) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGGN NO: 89) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 262) iPS: 421333 HV-73QVQLVESGGGVVQPGRSLR RYAMH VISYDGGNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRYAMHWVR (SEQ ID (SEQ ID NO: 113) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGGN NO: 90) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 263) iPS: 421340 HV-74QVQLVESGGGVVQPGRSLR RFAMH VISFDGGNKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 141) (SEQ ID NO: 171)QAPGKGLEWVAVISFDGGN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 264) iPS: 421347 HV-75QVQLVESGGGVVQPGRSLR RFAMH VISYDGANKYYARSVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 142) (SEQ ID NO: 171)QAPGKGLEWVAVISYDGAN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 265) iPS: 421354 HV-76QVQLVESGGGVVQPGRSLR RFAMH VISYDGGNKYYARSVKG GYDFLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 113) (SEQ ID NO: 173)QAPGKGLEWVAVISYDGGN NO: 88) KYYARSVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDFLTGYPDYWGQGTL VTVSS (SEQ ID NO: 266) iPS: 421361 HV-10QVQLVESGGGVVQPGRSLR RFAMH VISYDGGNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 106) (SEQ ID NO: 172)QAPGKGLEWVAVISYDGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 200) iPS: 421365 HV-10QVQLVESGGGVVQPGRSLR RFAMH VISYDGGNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 106) (SEQ ID NO: 172)QAPGKGLEWVAVISYDGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 200) iPS: 421369 HV-10QVQLVESGGGVVQPGRSLR RFAMH VISYDGGNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 106) (SEQ ID NO: 172)QAPGKGLEWVAVISYDGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 200) iPS: 421373 HV-77QVQLVESGGGVVQPGRSLR HFAMH VISYDGGNKYYAESVKG GYDILTGYPDYLSCAASGFTFSHFAMHWVR (SEQ ID (SEQ ID NO: 106) (SEQ ID NO: 172)QAPGKGLEWVAVISYDGGN NO: 89) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 267) iPS: 421380 HV-78QVQLVESGGGVVQPGRSLR RYAMH VISYDGGNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRYAMHWVR (SEQ ID (SEQ ID NO: 106) (SEQ ID NO: 172)QAPGKGLEWVAVISYDGGN NO: 90) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 268) iPS: 421387 HV-79QVQLVESGGGVVQPGRSLR RFAMH VISFDGGNKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 136) (SEQ ID NO: 172)QAPGKGLEWVAVISFDGGN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 269) iPS: 421394 HV-80QVQLVESGGGVVQPGRSLR RFAMH VISYDGANKYYAESVKG GYDILTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 137) (SEQ ID NO: 172)QAPGKGLEWVAVISYDGAN NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDILTGYPDYWGQGTL VTVSS (SEQ ID NO: 270) iPS: 421855 HV-81QVQLVESGGGVVQPGRSLR KYAMH VISFKGSNKYYAESVKG GYDLLTGYPDYLSCAASGFTFSKYAMHWVR (SEQ ID (SEQ ID NO: 143) (SEQ ID NO: 174)QAPGKGLEWVAVISFKGSN NO: 91) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDLLTGYPDYWGQGTL VTVSS (SEQ ID NO: 271) iPS: 421861 HV-82QVQLVESGGGVVQPGRSLR RYAMH VISYQGGNKYYAESVKG GYDLLTGYPDYLSCAASGFTFSRYAMHWVR (SEQ ID (SEQ ID NO: 109) (SEQ ID NO: 174)QAPGKGLEWVAVISYQGGN NO: 90) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDLLTGYPDYWGQGTL VTVSS (SEQ ID NO: 272) iPS: 421867 HV-83QVQLVESGGGVVQPGRSLR HFAMH VISFSGSNKYYAESVKG GYDMLTGYPDYLSCAASGFTFSHFAMHWVR (SEQ ID (SEQ ID NO: 144) (SEQ ID NO: 175)QAPGKGLEWVAVISFSGSNK NO: 89) YYAESVKGRFTISRDNSKNT LYLQMNSLRAEDTALFYCARGYDMLTGYPDYWGQGTL VTVSS (SEQ ID NO: 273) iPS: 421873 HV-84QVQLVESGGGVVQPGRSLR KFAMH VISYRGGNKYYAESVKG GYDLLTGYPDYLSCAASGFTFSKFAMHWVR (SEQ ID (SEQ ID NO: 145) (SEQ ID NO: 174)QAPGKGLEWVAVISYRGGN NO: 92) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDLLTGYPDYWGQGTL VTVSS (SEQ ID NO: 274) iPS: 421879 HV-85QVQLVESGGGVVQPGRSLR RYAMH VISYSGANKYYAESVKG GYDLLSGYPDYLSCAASGFTFSRYAMHWVR (SEQ ID (SEQ ID NO: 146) (SEQ ID NO: 176)QAPGKGLEWVAVISYSGAN NO: 90) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDLLSGYPDYWGQGTL VTVSS (SEQ ID NO: 275) iPS: 421885 HV-86QVQLVESGGGVVQPGRSLR HYAMH VISFKGANKYYAESVKG GYDLLTGYPDYLSCAASGFTFSHYAMHWVR (SEQ ID (SEQ ID NO: 147) (SEQ ID NO: 174)QAPGKGLEWVAVISFKGAN NO: 93) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDLLTGYPDYWGQGTL VTVSS (SEQ ID NO: 276) iPS: 421891 HV-87QVQLVESGGGVVQPGRSLR HYAMH VISYRGANKYYAESVKG GYDLLTGYPDYLSCAASGFTFSHYAMHWVR (SEQ ID (SEQ ID NO: 148) (SEQ ID NO: 174)QAPGKGLEWVAVISYRGAN NO: 93) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDLLTGYPDYWGQGTL VTVSS (SEQ ID NO: 277) iPS: 421897 HV-88QVQLVESGGGVVQPGRSLR HYAMH VISFYGSNKYYAESVKG GYDFLTGYPDYLSCAASGFTFSHYAMHWVR (SEQ ID (SEQ ID NO: 149) (SEQ ID NO: 173)QAPGKGLEWVAVISFYGSN NO: 93) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDFLTGYPDYWGQGTL VTVSS (SEQ ID NO: 278) iPS: 421903 HV-89QVQLVESGGGVVQPGRSLR HFAMH VISFFGGNKYYAESVKG GYDFLTGYPDYLSCAASGFTFSHFAMHWVR (SEQ ID (SEQ ID NO: 150) (SEQ ID NO: 173)QAPGKGLEWVAVISFFGGN NO: 89) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDFLTGYPDYWGQGTL VTVSS (SEQ ID NO: 279) iPS: 421909 HV-90QVQLVESGGGVVQPGRSLR HYAMH VISFMGTNKYYAESVKG GYDFLTGYPDYLSCAASGFTFSHYAMHWVR (SEQ ID (SEQ ID NO: 151) (SEQ ID NO: 173)QAPGKGLEWVAVISFMGTN NO: 93) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDFLTGYPDYWGQGTL VTVSS (SEQ ID NO: 280) iPS: 421915 HV-91QVQLVESGGGVVQPGRSLR YFAMH VISHRGTNKYYAESVKG GYDLLSGYPDYLSCAASGFTFSYFAMHWVR (SEQ ID (SEQ ID NO: 152) (SEQ ID NO: 176)QAPGKGLEWVAVISHRGTN NO: 94) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDLLSGYPDYWGQGTL VTVSS (SEQ ID NO: 281) iPS: 480711 HV-92QVQLVESGGGVVQPGRSLR RFAMH VINYRGHGKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 153) (SEQ ID NO: 171)QAPGKGLEWVGVINYRGHG NO: 88) KYYAESVKGRFTVSRDNSK NTLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQG TLVTVSS (SEQ ID NO: 282) iPS: 480706 HV-93QVQLVESGGGVVQPGRSLR RFAMH VISFSGGSKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 154) (SEQ ID NO: 171)QAPGKGLEWVGVISFSGGSK NO: 88) YYAESVKGRFTLSRDNSKNT LYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTLV TVSS (SEQ ID NO: 283) iPS: 480713 HV-94QVQLVESGGGVVQPGRSLR RFAMH VISYTGQFKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 155) (SEQ ID NO: 171)QAPGKGLEWVGVISYTGQF NO: 88) KYYAESVKGRFTVSRDNSK NTLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQG TLVTVSS (SEQ ID NO: 284) iPS: 480705 HV-95QVQLVESGGGVVQPGRSLR RFAMH VISYTGAQKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 156) (SEQ ID NO: 171)QAPGKGLEWVGVISYTGAQ NO: 88) KYYAESVKGRFTMSRDNSK NTLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQG TLVTVSS (SEQ ID NO: 285) iPS: 480707 HV-96QVQLVESGGGVVQPGRSLR RFAMH VISYSGASKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 157) (SEQ ID NO: 171)QAPGKGLEWVGVISYSGAS NO: 88) KYYAESVKGRFTMSRDNSK NTLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQG TLVTVSS (SEQ ID NO: 286) iPS: 480708 HV-97QVQLVESGGGVVQPGRSLR RFAMH VISYSGAFKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 158) (SEQ ID NO: 171)QAPGKGLEWVAVISYSGAF NO: 88) KYYAESVKGRFTVSRDNSK NTLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQG TLVTVSS (SEQ ID NO: 287) iPS: 480709 HV-98QVQLVESGGGVVQPGRSLR RFAMH VITYTGGAKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 159) (SEQ ID NO: 171)QAPGKGLEWVGVITYTGGA NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 288) iPS: 480712 HV-99QVQLVESGGGVVQPGRSLR RFAMH VINFQGTTKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 160) (SEQ ID NO: 171)QAPGKGLEWVGVINFQGTT NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 289) iPS: 480704 HV-100QVQLVESGGGVVQPGRSLR RFAMH VISYSGDLKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 161) (SEQ ID NO: 171)QAPGKGLEWVGVISYSGDL NO: 88) KYYAESVKGRFTVSRDNSK NTLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQG TLVTVSS (SEQ ID NO: 290) iPS: 480710 HV-101QVQLVESGGGVVQPGRSLR RFAMH VINYFGDAKYYAESVKG GYDVLTGYPDYLSCAASGFTFSRFAMHWVR (SEQ ID (SEQ ID NO: 162) (SEQ ID NO: 171)QAPGKGLEWVGVINYFGDA NO: 88) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDVLTGYPDYWGQGTL VTVSS (SEQ ID NO: 291) iPS: 480716 HV-102QVQLVESGGGVVQPGRSLR FYAMH VISSFGSNKYYAESVKG GYDLLTGYPDYLSCAASGFTFSFYAMHWVR (SEQ ID (SEQ ID NO: 163) (SEQ ID NO: 174)QAPGKGLEWVAVISSFGSNK NO: 95) YYAESVKGRFTISRDNSKNT LYLQMNSLRAEDTALFYCARGYDLLTGYPDYWGQGTLV TVSS (SEQ ID NO: 292) iPS: 480715 HV-103QVQLVESGGGVVQPGRSLR YYAMH VISYSGSNKYYAESVKG GYDLLTGYPDYLSCAASGFTFSYYAMHWVR (SEQ ID (SEQ ID NO: 164) (SEQ ID NO: 174)QAPGKGLEWVAVISYSGSN NO: 96) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDLLTGYPDYWGQGTL VTVSS (SEQ ID NO: 293) iPS: 480717 HV-104QVQLVESGGGVVQPGRSLR YYAMH VISHYGTNKYYAESVKG GYDPLTGYPDYLSCAASGFTFSYYAMHWVR (SEQ ID (SEQ ID NO: 165) (SEQ ID NO: 177)QAPGKGLEWVAVISHYGTN NO: 96) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDPLTGYPDYWGQGTL VTVSS (SEQ ID NO: 294) iPS: 480714 HV-105QVQLVESGGGVVQPGRSLR HYAMH VISYQGSNKYYAESVKG GYDLLTGYPDYLSCAASGFTFSHYAMHWVR (SEQ ID (SEQ ID NO: 166) (SEQ ID NO: 174)QAPGKGLEWVAVISYQGSN NO: 93) KYYAESVKGRFTISRDNSKN TLYLQMNSLRAEDTALFYCARGYDLLTGYPDYWGQGTL VTVSS (SEQ ID NO: 295) 19H8 variants 19H8 HV-106QVQLQQSGPGLVKPSQTLSL SNSATWN RTYYRSKWSNHYAVSVKS GTWKQLWFLDHTCAISGDSVSSNSATWNWIR (SEQ ID (SEQ ID NO: 167) (SEQ ID NO: 178)QSPSRGLEWLGRTYYRSKW NO: 97) SNHYAVSVKSRITINPDTSKS QFSLQLNSVTPEDTAVYYCARGTWKQLWFLDHWGQGTL VTVSS (SEQ ID NO: 296) iPS: 448202 HV-107QVQLQQSGPGLVKPSQTLSL NRLATWN RTYYRGKWKNHYAVSVKS GTWNQDWFLDHTCAISGDSVSNRLATWNWIR (SEQ ID (SEQ ID NO: 168) (SEQ ID NO: 179)QSPSRGLEWLGRTYYRGKW NO: 98) KNHYAVSVKSRITINPDTSKS QFSLQLNSVTPEDTAVYYCARGTWNQDWFLDHWGQGTL VTVSS (SEQ ID NO: 297) iPS: 449375 HV-108QVQLQQSGPGLVKPSQTLSL NRLATWN RTYYRGKWKNHYAVSVKS GTWDQDWFLDHTCAISGDSVSNRLATWNWIR (SEQ ID (SEQ ID NO: 168) (SEQ ID NO: 180)QSPSRGLEWLGRTYYRGKW NO: 98) KNHYAVSVKSRITINPDTSKS QFSLQLNSVTPEDTAVYYCARGTWDQDWFLDHWGQGTL VTVSS (SEQ ID NO: 298) iPS: 448083 HV-109QVQLQQSGPGLVKPSQTLSL SRQATWN RTYYRGKWKNHYAVSVKS GTWEQDWFLDHTCAISGDSVSSRQATWNWIR (SEQ ID (SEQ ID NO: 168) (SEQ ID NO: 181)QSPSRGLEWLGRTYYRGKW NO: 99) KNHYAVSVKSRITINPDTSKS QFSLQLNSVTPEDTAVYYCARGTWEQDWFLDHWGQGTL VTVSS (SEQ ID NO: 299) iPS: 452128 HV-110QVQLQQSGPGLVKPSQTLSL NKQATWN RTYYRGKWKNHYAVSVKS GMWNQNWFLDHTCAISGDSVSNKQATWNWIR (SEQ ID (SEQ ID NO: 168) (SEQ ID NO: 182)QSPSRGLEWLGRTYYRGKW NO: 100) KNHYAVSVKSRITINPDTSKS QFSLQLNSVTPEDTAVYYCARGMWNQNWFLDHWGQGTL VTVSS (SEQ ID NO: 300) iPS: 448195 HV-110QVQLQQSGPGLVKPSQTLSL NKQATWN RTYYRGKWKNHYAVSVKS GMWNQNWFLDHTCAISGDSVSNKQATWNWIR (SEQ ID (SEQ ID NO: 168) (SEQ ID NO: 182)QSPSRGLEWLGRTYYRGKW NO: 100) KNHYAVSVKSRITINPDTSKS QFSLQLNSVTPEDTAVYYCARGMWNQNWFLDHWGQGTL VTVSS (SEQ ID NO: 300) iPS: 448466 HV-111QVQLQQSGPGLVKPSQTLSL NKQATWN RTYYRGQWKNHYAVSVKS GTWIGDWFMDHTCAISGDSVSNKQATWNWIR (SEQ ID (SEQ ID NO: 169) (SEQ ID NO: 183)QSPSRGLEWLGRTYYRGQW NO: 100) KNHYAVSVKSRITINPDTSKS QFSLQLNSVTPEDTAVYYCARGTWIGDWFMDHWGQGTL VTVSS (SEQ ID NO: 301) iPS: 448689 HV-107QVQLQQSGPGLVKPSQTLSL NRLATWN RTYYRGKWKNHYAVSVKS GTWNQDWFLDHTCAISGDSVSNRLATWNWIR (SEQ ID (SEQ ID NO: 168) (SEQ ID NO: 179)QSPSRGLEWLGRTYYRGKW NO: 98) KNHYAVSVKSRITINPDTSKS QFSLQLNSVTPEDTAVYYCARGTWNQDWFLDHWGQGTL VTVSS (SEQ ID NO: 297) iPS: 449034 HV-112QVQLQQSGPGLVKPSQTLSL NKQATWN RTYYRGKWKNHYAVSVKS GTWIQDWFLDHTCAISGDSVSNKQATWNWIR (SEQ ID (SEQ ID NO: 168) (SEQ ID NO: 184)QSPSRGLEWLGRTYYRGKW NO: 100) KNHYAVSVKSRITINPDTSKS QFSLQLNSVTPEDTAVYYCARGTWIQDWFLDHWGQGTL VTVSS (SEQ ID NO: 302) iPS: 448075 HV-113QVQLQQSGPGLVKPSQTLSL SNHATWN RTYYRGKWKNHYAVSVKS GTWDQDWFLDHTCAISGDSVSSNHATWNWIR (SEQ ID (SEQ ID NO: 168) (SEQ ID NO: 180)QSPSRGLEWLGRTYYRGKW NO: 101) KNHYAVSVKSRITINPDTSKS QFSLQLNSVTPEDTAVYYCARGTWDQDWFLDHWGQGTL VTVSS (SEQ ID NO: 303) iPS: 448924 HV-114QVQLQQSGPGLVKPSQTLSL SRYATWN RTYYRGQWKNHYAVSVKS GMWNQNWFLDHTCAISGDSVSSRYATWNWIR (SEQ ID (SEQ ID NO: 169) (SEQ ID NO: 182)QSPSRGLEWLGRTYYRGQW NO: 102) KNHYAVSVKSRITINPDTSKS QFSLQLNSVTPEDTAVYYCARGMWNQNWFLDHWGQGTL VTVSS (SEQ ID NO: 304) iPS: 448752 HV-110QVQLQQSGPGLVKPSQTLSL NKQATWN RTYYRGKWKNHYAVSVKS GMWNQNWFLDHTCAISGDSVSNKQATWNWIR (SEQ ID (SEQ ID NO: 168) (SEQ ID NO: 182)QSPSRGLEWLGRTYYRGKW NO: 100) KNHYAVSVKSRITINPDTSKS QFSLQLNSVTPEDTAVYYCARGMWNQNWFLDHWGQGTL VTVSS (SEQ ID NO: 300) iPS: 448772 HV-115QVQLQQSGPGLVKPSQTLSL NKQATWN RTYYRGKWKNHYAVSVKS GMWSGDWFLDHTCAISGDSVSNKQATWNWIR (SEQ ID (SEQ ID NO: 168) (SEQ ID NO: 185)QSPSRGLEWLGRTYYRGKW NO: 100) KNHYAVSVKSRITINPDTSKS QFSLQLNSVTPEDTAVYYCARGMWSGDWFLDHWGQGTL VTVSS (SEQ ID NO: 305) iPS: 448117 HV-116QVQLQQSGPGLVKPSQTLSL SHVATWN RTYYRGKWKNHYAVSVKS GMWSEDWFLDHTCAISGDSVSSHVATWNWIR (SEQ ID (SEQ ID NO: 168) (SEQ ID NO: 186)QSPSRGLEWLGRTYYRGKW NO: 103) KNHYAVSVKSRITINPDTSKS QFSLQLNSVTPEDTAVYYCARGMWSEDWFLDHWGQGTL VTVSS (SEQ ID NO: 306) iPS: 448788 HV-117QVQLQQSGPGLVKPSQTLSL SRQATWN RTYYRGKWKNHYAVSVKS GMWQGNWFLDHTCAISGDSVSSRQATWNWIR (SEQ ID (SEQ ID NO: 168) (SEQ ID NO: 187)QSPSRGLEWLGRTYYRGKW NO: 99) KNHYAVSVKSRITINPDTSKS QFSLQLNSVTPEDTAVYYCARGMWQGNWFLDHWGQGTL VTVSS (SEQ ID NO: 307) iPS: 448593 HV-118QVQLQQSGPGLVKPSQTLSL NHQATWN RTYYRGKWKNHYAVSVKS GTWIQDWFLDHTCAISGDSVSNHQATWNWIR (SEQ ID (SEQ ID NO: 168) (SEQ ID NO: 184)QSPSRGLEWLGRTYYRGKW NO: 104) KNHYAVSVKSRITINPDTSKS QFSLQLNSVTPEDTAVYYCARGTWIQDWFLDHWGQGTL VTVSS (SEQ ID NO: 308) iPS: 448238 HV-119QVQLQQSGPGLVKPSQTLSL SRDATWN RTYYRGKWKNHYAVSVKS GQWNEDWFLDHTCAISGDSVSSRDATWNWIR (SEQ ID (SEQ ID NO: 168) (SEQ ID NO: 188)QSPSRGLEWLGRTYYRGKW NO: 105) KNHYAVSVKSRITINPDTSKS QFSLQLNSVTPEDTAVYYCARGQWNEDWFLDHWGQGTL VTVSS (SEQ ID NO: 309) iPS: 448901 HV-120QVQLQQSGPGLVKPSQTLSL NRLATWN RTYYRGKWKNHYAVSVKS GRWEGDWFFDHTCAISGDSVSNRLATWNWIR (SEQ ID (SEQ ID NO: 168) (SEQ ID NO: 189)QSPSRGLEWLGRTYYRGKW NO: 98) KNHYAVSVKSRITINPDTSKS QFSLQLNSVTPEDTAVYYCARGRWEGDWFFDHWGQGTL VTVSS (SEQ ID NO: 310) iPS: 448655 HV-121QVQLQQSGPGLVKPSQTLSL NKQATWN RTYFRRTWKNHYAVSVKS GMWSEDWFLDHTCAISGDSVSNKQATWNWIR (SEQ ID (SEQ ID NO: 170) (SEQ ID NO: 186)QSPSRGLEWLGRTYFRRTW NO: 100) KNHYAVSVKSRITINPDTSKS QFSLQLNSVTPEDTAVYYCARGMWSEDWFLDHWGQGTL VTVSS (SEQ ID NO: 311) iPS: 448730 HV-122QVQLQQSGPGLVKPSQTLSL NRLATWN RTYYRGKWKNHYAVSVKS GVWIGNVVFLDHTCAISGDSVSNRLATWNWIR (SEQ ID (SEQ ID NO: 168) (SEQ ID NO: 190)QSPSRGLEWLGRTYYRGKW NO: 98) KNHYAVSVKSRITINPDTSKS QFSLQLNSVTPEDTAVYYCARGVWIGNWFLDHWGQGTL VTVSS (SEQ ID NO: 312) iPS: 449027 HV-110QVQLQQSGPGLVKPSQTLSL NKQATWN RTYYRGKWKNHYAVSVKS GMWNQNWFLDHTCAISGDSVSNKQATWNWIR (SEQ ID (SEQ ID NO: 168) (SEQ ID NO: 182)QSPSRGLEWLGRTYYRGKW NO: 100) KNHYAVSVKSRITINPDTSKS QFSLQLNSVTPEDTAVYYCARGMWNQNWFLDHWGQGTL VTVSS (SEQ ID NO: 300) 3574 HV-110QVQLQQSGPGLVKPSQTLSL NKQATWN RTYYRGKWKNHYAVSVKS GMWNQNWFLDHTCAISGDSVSNKQATWNWIR (SEQ ID (SEQ ID NO: 168) (SEQ ID NO: 182)QSPSRGLEWLGRTYYRGKW NO: 100) KNHYAVSVKSRITINPDTSKS QFSLQLNSVTPEDTAVYYCARGMWNQNWFLDHWGQGTL VTVSS (SEQ ID NO: 300) 3575 HV-106QVQLQQSGPGLVKPSQTLSL SNSATWN RTYYRSKWSNHYAVSVKS GTWKQLWFLDHTCAISGDSVSSNSATWNWIR (SEQ ID (SEQ ID NO: 167) (SEQ ID NO: 178)QSPSRGLEWLGRTYYRSKW NO: 97) SNHYAVSVKSRITINPDTSKS QFSLQLNSVTPEDTAVYYCARGTWKQLWFLDHWGQGTL VTVSS (SEQ ID NO: 296)

The anti-PAC1 antibodies or antigen-binding fragments of the inventionmay comprise one or more of the light chain CDRs (i.e. CDRLs) and/orheavy chain CDRs (i.e. CDRHs) presented in Tables 1A and 1B,respectively. In some embodiments, the anti-PAC1 antibodies or bindingfragments thereof are derived from antibody 29G4v9, 29G4v10, or 29G4v22(i.e. has one or more substitutions in one or more of the CDRLs and/orCDRHs of the 29G4v9, 29G4v10, or 29G4v22 antibody). For instance, incertain embodiments, the anti-PAC1 antibodies or antigen-bindingfragments comprise one or more light chain CDRs selected from (i) aCDRL1 selected from SEQ ID NOs: 5 to 16, (ii) a CDRL2 of SEQ ID NO: 26,and (iii) a CDRL3 selected from SEQ ID NOs: 36 to 38, and (iv) a CDRL of(i), (ii) and (iii) that contains one or more, e.g., one, two, three,four or more amino acid substitutions (e.g., conservative amino acidsubstitutions), deletions or insertions of no more than five, four,three, two, or one amino acids. In these and other embodiments, theanti-PAC1 antibodies or antigen-binding fragments comprise one or moreheavy chain CDRs selected from (i) a CDRH1 selected from SEQ ID NOs: 88to 96, (ii) a CDRH2 selected from SEQ ID NOs: 106 to 166, and (iii) aCDRH3 selected from SEQ ID NOs: 171 to 177, and (iv) a CDRH of (i), (ii)and (iii) that contains one or more, e.g., one, two, three, four or moreamino acid substitutions (e.g., conservative amino acid substitutions),deletions or insertions of no more than five, four, three, two, or oneamino acids amino acids.

In other embodiments, the anti-PAC1 antibodies or binding fragmentsthereof are derived from antibody 19H8 (i.e. has one or moresubstitutions in one or more of the CDRLs and/or CDRHs of the 19H8antibody). In such embodiments, the anti-PAC1 antibodies orantigen-binding fragments comprise one or more light chain CDRs selectedfrom (i) a CDRL1 selected from SEQ ID NOs: 17 to 25, (ii) a CDRL2selected from SEQ ID NOs: 27 to 35, and (iii) a CDRL3 selected from SEQID NOs: 39 to 51, and (iv) a CDRL of (i), (ii) and (iii) that containsone or more, e.g., one, two, three, four or more amino acidsubstitutions (e.g., conservative amino acid substitutions), deletionsor insertions of no more than five, four, three, two, or one aminoacids. In these and other embodiments, the anti-PAC1 antibodies orantigen-binding fragments comprise one or more heavy chain CDRs selectedfrom (i) a CDRH1 selected from SEQ ID NOs: 97 to 105, (ii) a CDRH2selected from SEQ ID NOs: 167 to 170, and (iii) a CDRH3 selected fromSEQ ID NOs: 178 to 190, and (iv) a CDRH of (i), (ii) and (iii) thatcontains one or more, e.g., one, two, three, four or more amino acidsubstitutions (e.g., conservative amino acid substitutions), deletionsor insertions of no more than five, four, three, two, or one amino acidsamino acids.

In certain embodiments, the anti-PAC1 antibodies or antigen-bindingfragments may comprise 1, 2, 3, 4, 5, or 6 variant forms of the CDRslisted in Tables 1A and 1B, each having at least 80%, 85%, 90% or 95%sequence identity to a CDR sequence listed in Tables 1A and 1B. In someembodiments, the anti-PAC1 antibodies or antigen-binding fragmentsinclude 1, 2, 3, 4, 5, or 6 of the CDRs listed in Tables 1A and 1B, eachdiffering by no more than 1, 2, 3, 4 or 5 amino acids from the CDRslisted in these tables. In some embodiments, the anti-PAC1 antibodies orantigen-binding fragments of the invention comprise a CDRL1 comprising asequence selected from SEQ ID NOs: 5 to 16 or a variant thereof havingone, two, three or four amino acid substitutions; a CDRL2 comprising thesequence of SEQ ID NO: 26 or a variant thereof having one, two, three orfour amino acid substitutions; a CDRL3 comprising a sequence selectedfrom SEQ ID NOs: 36 to 38 or a variant thereof having one, two, three orfour amino acid substitutions; a CDRH1 comprising a sequence selectedfrom SEQ ID NOs: 88 to 96 or a variant thereof having one, two, three orfour amino acid substitutions; a CDRH2 comprising a sequence selectedfrom SEQ ID NOs: 106 to 166 or a variant thereof having one, two, threeor four amino acid substitutions; and a CDRH3 comprising a sequenceselected from SEQ ID NOs: 171 to 177 or a variant thereof having one,two, three or four amino acid substitutions. In other embodiments, theanti-PAC1 antibodies or antigen-binding fragments of the inventioncomprise a CDRL1 comprising a sequence selected from SEQ ID NOs: 5 to16; a CDRL2 comprising the sequence of SEQ ID NO: 26; a CDRL3 comprisinga sequence selected from SEQ ID NOs: 36 to 38; a CDRH1 comprising asequence selected from SEQ ID NOs: 88 to 96; a CDRH2 comprising asequence selected from SEQ ID NOs: 106 to 166; and a CDRH3 comprising asequence selected from SEQ ID NOs: 171 to 177.

In other embodiments, the anti-PAC1 antibodies or antigen-bindingfragments of the invention comprise a CDRL1 comprising a sequenceselected from SEQ ID NOs: 17 to 25 or a variant thereof having one, two,three or four amino acid substitutions; a CDRL2 comprising a sequenceselected from SEQ ID NOs: 27 to 35 or a variant thereof having one, two,three or four amino acid substitutions; a CDRL3 comprising a sequenceselected from SEQ ID NOs: 39 to 51 or a variant thereof having one, two,three or four amino acid substitutions; a CDRH1 comprising a sequenceselected from SEQ ID NOs: 97 to 105 or a variant thereof having one,two, three or four amino acid substitutions; a CDRH2 comprising asequence selected from SEQ ID NOs: 167 to 170 or a variant thereofhaving one, two, three or four amino acid substitutions; and a CDRH3comprising a sequence selected from SEQ ID NOs: 178 to 190 or a variantthereof having one, two, three or four amino acid substitutions. Inother embodiments, the anti-PAC1 antibodies or antigen-binding fragmentsof the invention comprise a CDRL1 comprising a sequence selected fromSEQ ID NOs: 17 to 25; a CDRL2 comprising a sequence selected from SEQ IDNOs: 27 to 35; a CDRL3 comprising a sequence selected from SEQ ID NOs:39 to 51; a CDRH1 comprising a sequence selected from SEQ ID NOs: 97 to105; a CDRH2 comprising a sequence selected from SEQ ID NOs: 167 to 170;and a CDRH3 comprising a sequence selected from SEQ ID NOs: 178 to 190.

In particular embodiments, the anti-PAC1 antibodies or antigen-bindingfragments of the invention comprise a light chain variable regioncomprising a CDRL1, a CDRL2, and a CDRL3, wherein: (a) CDRL1, CDRL2, andCDRL3 have the sequence of SEQ ID NOs: 7, 26, and 36, respectively; (b)CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 5, 26, and 36,respectively; (c) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ IDNOs: 12, 26, and 36, respectively; or (d) CDRL1, CDRL2, and CDRL3 havethe sequence of SEQ ID NOs: 13, 26, and 36, respectively.

In other particular embodiments, the anti-PAC1 antibodies orantigen-binding fragments of the invention comprise a heavy chainvariable region comprising a CDRH1, a CDRH2, and a CDRH3, wherein: (a)CDRH1, CDRH2, and CDRH3 have the sequence of SEQ ID NOs: 88, 108, and171, respectively; (b) CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 88, 116, and 171, respectively; (c) CDRH1, CDRH2, and CDRH3 havethe sequence of SEQ ID NOs: 88, 134, and 171, respectively; (d) CDRH1,CDRH2, and CDRH3 have the sequence of SEQ ID NOs: 92, 145, and 174,respectively; (e) CDRH1, CDRH2, and CDRH3 have the sequence of SEQ IDNOs: 88, 108, and 172, respectively; (f) CDRH1, CDRH2, and CDRH3 havethe sequence of SEQ ID NOs: 88, 128, and 172, respectively; (g) CDRH1,CDRH2, and CDRH3 have the sequence of SEQ ID NOs: 88, 153, and 171,respectively; (i) CDRH1, CDRH2, and CDRH3 have the sequence of SEQ IDNOs: 88, 154, and 171, respectively; or (j) CDRH1, CDRH2, and CDRH3 havethe sequence of SEQ ID NOs: 88, 155, and 171, respectively.

In certain embodiments, the anti-PAC1 antibodies or antigen-bindingfragments of the invention comprise a light chain variable regioncomprising a CDRL1, a CDRL2, and a CDRL3 and a heavy chain variableregion comprising a CDRH1, a CDRH2, and a CDRH3, wherein:

(a) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 7, 26, and36, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 88, 108, and 171, respectively;

(b) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 7, 26, and36, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 88, 116, and 171, respectively;

(c) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 5, 26, and36, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 88, 134, and 171, respectively;

(d) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 5, 26, and36, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 92, 145, and 174, respectively;

(e) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 7, 26, and36, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 88, 108, and 172, respectively;

(f) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 5, 26, and36, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 88, 128, and 172, respectively;

(g) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 7, 26, and36, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 88, 134, and 171, respectively;

(h) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 12, 26, and36, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 88, 153, and 171, respectively;

(i) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 12, 26, and36, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 88, 154, and 171, respectively; or

(j) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 13, 26, and36, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 88, 155, and 171, respectively.

In one embodiment, the anti-PAC1 antibody or antigen-binding fragmentthereof comprises a light chain variable region comprising a CDRL1, aCDRL2, and a CDRL3 and a heavy chain variable region comprising a CDRH1,a CDRH2, and a CDRH3, wherein CDRL1, CDRL2, and CDRL3 have the sequenceof SEQ ID NOs: 7, 26, and 36, respectively, and CDRH1, CDRH2, and CDRH3have the sequence of SEQ ID NOs: 88, 108, and 171, respectively. Inanother embodiment, the anti-PAC1 antibody or antigen-binding fragmentthereof comprises a light chain variable region comprising a CDRL1, aCDRL2, and a CDRL3 and a heavy chain variable region comprising a CDRH1,a CDRH2, and a CDRH3, wherein CDRL1, CDRL2, and CDRL3 have the sequenceof SEQ ID NOs: 7, 26, and 36, respectively, and CDRH1, CDRH2, and CDRH3have the sequence of SEQ ID NOs: 88, 116, and 171, respectively. In yetanother embodiment, the anti-PAC1 antibody or antigen-binding fragmentthereof comprises a light chain variable region comprising a CDRL1, aCDRL2, and a CDRL3 and a heavy chain variable region comprising a CDRH1,a CDRH2, and a CDRH3, wherein CDRL1, CDRL2, and CDRL3 have the sequenceof SEQ ID NOs: 5, 26, and 36, respectively, and CDRH1, CDRH2, and CDRH3have the sequence of SEQ ID NOs: 88, 134, and 171, respectively. Instill another embodiment, the anti-PAC1 antibody or antigen-bindingfragment thereof comprises a light chain variable region comprising aCDRL1, a CDRL2, and a CDRL3 and a heavy chain variable region comprisinga CDRH1, a CDRH2, and a CDRH3, wherein CDRL1, CDRL2, and CDRL3 have thesequence of SEQ ID NOs: 5, 26, and 36, respectively, and CDRH1, CDRH2,and CDRH3 have the sequence of SEQ ID NOs: 92, 145, and 174,respectively. In one particular embodiment, the anti-PAC1 antibody orantigen-binding fragment thereof comprises a light chain variable regioncomprising a CDRL1, a CDRL2, and a CDRL3 and a heavy chain variableregion comprising a CDRH1, a CDRH2, and a CDRH3, wherein CDRL1, CDRL2,and CDRL3 have the sequence of SEQ ID NOs: 7, 26, and 36, respectively,and CDRH1, CDRH2, and CDRH3 have the sequence of SEQ ID NOs: 88, 108,and 172, respectively. In another particular embodiment, the anti-PAC1antibody or antigen-binding fragment thereof comprises a light chainvariable region comprising a CDRL1, a CDRL2, and a CDRL3 and a heavychain variable region comprising a CDRH1, a CDRH2, and a CDRH3, whereinCDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 12, 26, and 36,respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQ IDNOs: 88, 153, and 171, respectively.

In certain embodiments, the anti-PAC1 antibodies or antigen-bindingfragments of the invention comprise a light chain variable regioncomprising a CDRL1, a CDRL2, and a CDRL3, wherein: (a) CDRL1, CDRL2, andCDRL3 have the sequence of SEQ ID NOs: 25, 31, and 42, respectively; (b)CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 20, 30, and 44,respectively; (c) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ IDNOs: 17, 33, and 42, respectively; (d) CDRL1, CDRL2, and CDRL3 have thesequence of SEQ ID NOs: 23, 31, and 50, respectively; (e) CDRL1, CDRL2,and CDRL3 have the sequence of SEQ ID NOs: 17, 31, and 44, respectively;(f) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 17, 27, and39, respectively; (g) CDRL1, CDRL2, and CDRL3 have the sequence of SEQID NOs: 18, 31, and 46, respectively; (h) CDRL1, CDRL2, and CDRL3 havethe sequence of SEQ ID NOs: 17, 28, and 40, respectively; (i) CDRL1,CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 18, 30, and 43,respectively; or (j) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ IDNOs: 22, 28, and 49, respectively.

In certain other embodiments, the anti-PAC1 antibodies orantigen-binding fragments of the invention comprise a heavy chainvariable region comprising a CDRH1, a CDRH2, and a CDRH3, wherein: (a)CDRH1, CDRH2, and CDRH3 have the sequence of SEQ ID NOs: 98, 168, and190, respectively; (b) CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 100, 168, and 182, respectively; (c) CDRH1, CDRH2, and CDRH3have the sequence of SEQ ID NOs: 99, 168, and 187, respectively; (d)CDRH1, CDRH2, and CDRH3 have the sequence of SEQ ID NOs: 97, 167, and178, respectively; (e) CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 98, 168, and 189, respectively; (f) CDRH1, CDRH2, and CDRH3 havethe sequence of SEQ ID NOs: 98, 168, and 179, respectively; or (g)CDRH1, CDRH2, and CDRH3 have the sequence of SEQ ID NOs: 102, 169, and182, respectively.

In some embodiments, the anti-PAC1 antibodies or antigen-bindingfragments of the invention comprise a light chain variable regioncomprising a CDRL1, a CDRL2, and a CDRL3 and a heavy chain variableregion comprising a CDRH1, a CDRH2, and a CDRH3, wherein:

(a) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 25, 31, and42, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 98, 168, and 190, respectively;

(b) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 20, 30, and44, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 100, 168, and 182, respectively;

(c) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 17, 33, and42, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 99, 168, and 187, respectively;

(d) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 23, 31, and50, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 97, 167, and 178, respectively;

(e) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 17, 31, and44, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 98, 168, and 189, respectively;

(f) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 17, 27, and39, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 100, 168, and 182, respectively;

(g) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 18, 31, and46, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 98, 168, and 179, respectively;

(h) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 17, 28, and40, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 98, 168, and 179, respectively;

(i) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 18, 30, and43, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 100, 168, and 182, respectively; or

(j) CDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 22, 28, and49, respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQID NOs: 102, 169, and 182, respectively.

In one embodiment, the anti-PAC1 antibody or antigen-binding fragmentthereof comprises a light chain variable region comprising a CDRL1, aCDRL2, and a CDRL3 and a heavy chain variable region comprising a CDRH1,a CDRH2, and a CDRH3, wherein CDRL1, CDRL2, and CDRL3 have the sequenceof SEQ ID NOs: 25, 31, and 42, respectively, and CDRH1, CDRH2, and CDRH3have the sequence of SEQ ID NOs: 98, 168, and 190, respectively. Inanother embodiment, the anti-PAC1 antibody or antigen-binding fragmentthereof comprises a light chain variable region comprising a CDRL1, aCDRL2, and a CDRL3 and a heavy chain variable region comprising a CDRH1,a CDRH2, and a CDRH3, wherein CDRL1, CDRL2, and CDRL3 have the sequenceof SEQ ID NOs: 20, 30, and 44, respectively, and CDRH1, CDRH2, and CDRH3have the sequence of SEQ ID NOs: 100, 168, and 182, respectively. In yetanother embodiment, the anti-PAC1 antibody or antigen-binding fragmentthereof comprises a light chain variable region comprising a CDRL1, aCDRL2, and a CDRL3 and a heavy chain variable region comprising a CDRH1,a CDRH2, and a CDRH3, wherein CDRL1, CDRL2, and CDRL3 have the sequenceof SEQ ID NOs: 17, 33, and 42, respectively, and CDRH1, CDRH2, and CDRH3have the sequence of SEQ ID NOs: 99, 168, and 187, respectively. Instill another embodiment, the anti-PAC1 antibody or antigen-bindingfragment thereof comprises a light chain variable region comprising aCDRL1, a CDRL2, and a CDRL3 and a heavy chain variable region comprisinga CDRH1, a CDRH2, and a CDRH3, wherein CDRL1, CDRL2, and CDRL3 have thesequence of SEQ ID NOs: 23, 31, and 50, respectively, and CDRH1, CDRH2,and CDRH3 have the sequence of SEQ ID NOs: 97, 167, and 178,respectively. In one particular embodiment, the anti-PAC1 antibody orantigen-binding fragment thereof comprises a light chain variable regioncomprising a CDRL1, a CDRL2, and a CDRL3 and a heavy chain variableregion comprising a CDRH1, a CDRH2, and a CDRH3, wherein CDRL1, CDRL2,and CDRL3 have the sequence of SEQ ID NOs: 17, 31, and 44, respectively,and CDRH1, CDRH2, and CDRH3 have the sequence of SEQ ID NOs: 98, 168,and 189, respectively. In another particular embodiment, the anti-PAC1antibody or antigen-binding fragment thereof comprises a light chainvariable region comprising a CDRL1, a CDRL2, and a CDRL3 and a heavychain variable region comprising a CDRH1, a CDRH2, and a CDRH3, whereinCDRL1, CDRL2, and CDRL3 have the sequence of SEQ ID NOs: 17, 27, and 39,respectively, and CDRH1, CDRH2, and CDRH3 have the sequence of SEQ IDNOs: 100, 168, and 182, respectively.

In certain embodiments, the antibodies and antigen-binding fragments ofthe invention comprise an immunoglobulin heavy chain variable region(VH) and an immunoglobulin light chain variable region (VL) from anantibody that specifically binds to human PAC1, such as the antibodiesdescribed herein. The “variable region,” used interchangeably hereinwith “variable domain” (variable region of a light chain (VL), variableregion of a heavy chain (VH)), refers to the region in each of the lightand heavy immunoglobulin chains which is involved directly in bindingthe antibody to the antigen. As discussed above, the regions of variablelight and heavy chains have the same general structure and each regioncomprises four framework (FR) regions, the sequences of which are widelyconserved, connected by three CDRs. The framework regions adopt abeta-sheet conformation and the CDRs may form loops connecting thebeta-sheet structure. The CDRs in each chain are held in theirthree-dimensional structure by the framework regions and form, togetherwith the CDRs from the other chain, the antigen binding site.

Thus, in some embodiments, the anti-PAC1 antibodies and antigen-bindingfragments of the invention may comprise a light chain variable regionselected from LV-01 to LV-15, as shown in Table 1A, and/or a heavy chainvariable region selected from HV-01 to HV-105, as shown in Table 1B, andbinding fragments, derivatives, and variants of these light chain andheavy chain variable regions. In other embodiments, the anti-PAC1antibodies and antigen-binding fragments of the invention may comprise alight chain variable region selected from LV-16 to LV-36, as shown inTable 1A, and/or a heavy chain variable region selected from HV-106 toHV-122, as shown in Table 1B, and binding fragments, derivatives, andvariants of these light chain and heavy chain variable regions.

Each of the light chain variable regions listed in Table 1A may becombined with any of the heavy chain variable regions listed in Table 1Bto form an anti-PAC1 antibody or antigen-binding fragment thereof of theinvention. Examples of such combinations include, but are not limitedto: (i) LV-03 and any one of HV-03 to HV-26, HV-32 to HV-47, and HV-57to HV-62; (ii) LV-04 and any one of HV-11 to HV-91; (iii) LV-05 and anyone of HV-01, HV-03, HV-07, HV-09, and HV-10; (iv) LV-06 and any one ofHV-01, HV-03, HV-07, HV-09, and HV-10; (v) LV-07 and any one of HV-01,HV-03, HV-07, HV-09, and HV-10; (vi) LV-08 and HV-01; (vii) LV-09 andHV-01; (viii) LV-10 and HV-01; (ix) LV-11 and any one of HV-92, HV-93,HV-95 to HV-97, and HV-99 to HV-101; (x) LV-12 and HV-94; (xi) LV-13 andHV-98; (xii) LV-14 and any one of HV-102 to HV-104; (xiii) LV-15 andHV-105; (xiv) LV-17 and HV-107; (xv) LV-18 and HV-108; (xvi) LV-19 andHV-109; (xvii) LV-20 and HV-110; (xviii) LV-21 and HV-110; (xix) LV-22and HV-111; (xx) LV-23 and HV-107; (xxi) LV-24 and HV-112; (xxii) LV-25and HV-113; (xxiii) LV-26 and HV-114; (xxiv) LV-27 and HV-106 or HV-110;(xxv) LV-28 and HV-115 or HV-118; (xxvi) LV-29 and HV-116; (xxvii) LV-30and HV-117; (xxviii) LV-31 and HV-119; (xxix) LV-32 and HV-120; (xxx)LV-33 and HV-121; (xxxi) LV-34 and HV-122; (xxxii) LV-35 and HV-110; and(xxxiii) LV-36 and HV-110.

In certain embodiments, the anti-PAC1 antibodies or antigen-bindingfragments of the invention comprise a light chain variable regioncomprising the sequence of LV-03 (SEQ ID NO: 54) and a heavy chainvariable region comprising the sequence of HV-04 (SEQ ID NO: 194). Insome embodiments, the anti-PAC1 antibodies or antigen-binding fragmentsof the invention comprise a light chain variable region comprising thesequence of LV-03 (SEQ ID NO: 54) and a heavy chain variable regioncomprising the sequence of HV-13 (SEQ ID NO: 203). In other embodiments,the anti-PAC1 antibodies or antigen-binding fragments of the inventioncomprise a light chain variable region comprising the sequence of LV-04(SEQ ID NO: 55) and a heavy chain variable region comprising thesequence of HV-38 (SEQ ID NO: 228). In still other embodiments, theanti-PAC1 antibodies or antigen-binding fragments of the inventioncomprise a light chain variable region comprising the sequence of LV-04(SEQ ID NO: 55) and a heavy chain variable region comprising thesequence of HV-84 (SEQ ID NO: 274). In some embodiments, the anti-PAC1antibodies or antigen-binding fragments of the invention comprise alight chain variable region comprising the sequence of LV-03 (SEQ ID NO:54) and a heavy chain variable region comprising the sequence of HV-24(SEQ ID NO: 214). In certain embodiments, the anti-PAC1 antibodies orantigen-binding fragments of the invention comprise a light chainvariable region comprising the sequence of LV-04 (SEQ ID NO: 55) and aheavy chain variable region comprising the sequence of HV-50 (SEQ ID NO:240). In one embodiment, the anti-PAC1 antibodies or antigen-bindingfragments of the invention comprise a light chain variable regioncomprising the sequence of LV-03 (SEQ ID NO: 54) and a heavy chainvariable region comprising the sequence of HV-38 (SEQ ID NO: 228). Inanother embodiment, the anti-PAC1 antibodies or antigen-bindingfragments of the invention comprise a light chain variable regioncomprising the sequence of LV-11 (SEQ ID NO: 62) and a heavy chainvariable region comprising the sequence of HV-92 (SEQ ID NO: 282). Inyet another embodiment, the anti-PAC1 antibodies or antigen-bindingfragments of the invention comprise a light chain variable regioncomprising the sequence of LV-11 (SEQ ID NO: 62) and a heavy chainvariable region comprising the sequence of HV-93 (SEQ ID NO: 283). Instill another embodiment, the anti-PAC1 antibodies or antigen-bindingfragments of the invention comprise a light chain variable regioncomprising the sequence of LV-12 (SEQ ID NO: 63) and a heavy chainvariable region comprising the sequence of HV-94 (SEQ ID NO: 284).

In certain other embodiments, the anti-PAC1 antibodies orantigen-binding fragments of the invention comprise a light chainvariable region comprising the sequence of LV-34 (SEQ ID NO: 85) and aheavy chain variable region comprising the sequence of HV-122 (SEQ IDNO: 312). In some embodiments, the anti-PAC1 antibodies orantigen-binding fragments of the invention comprise a light chainvariable region comprising the sequence of LV-21 (SEQ ID NO: 72) and aheavy chain variable region comprising the sequence of HV-110 (SEQ IDNO: 300). In other embodiments, the anti-PAC1 antibodies orantigen-binding fragments of the invention comprise a light chainvariable region comprising the sequence of LV-30 (SEQ ID NO: 81) and aheavy chain variable region comprising the sequence of HV-117 (SEQ IDNO: 307). In still other embodiments, the anti-PAC1 antibodies orantigen-binding fragments of the invention comprise a light chainvariable region comprising the sequence of LV-27 (SEQ ID NO: 78) and aheavy chain variable region comprising the sequence of HV-106 (SEQ IDNO: 296). In some embodiments, the anti-PAC1 antibodies orantigen-binding fragments of the invention comprise a light chainvariable region comprising the sequence of LV-32 (SEQ ID NO: 83) and aheavy chain variable region comprising the sequence of HV-120 (SEQ IDNO: 310). In certain embodiments, the anti-PAC1 antibodies orantigen-binding fragments of the invention comprise a light chainvariable region comprising the sequence of LV-36 (SEQ ID NO: 87) and aheavy chain variable region comprising the sequence of HV-110 (SEQ IDNO: 300). In one embodiment, the anti-PAC1 antibodies or antigen-bindingfragments of the invention comprise a light chain variable regioncomprising the sequence of LV-23 (SEQ ID NO: 74) and a heavy chainvariable region comprising the sequence of HV-107 (SEQ ID NO: 297). Inanother embodiment, the anti-PAC1 antibodies or antigen-bindingfragments of the invention comprise a light chain variable regioncomprising the sequence of LV-17 (SEQ ID NO: 68) and a heavy chainvariable region comprising the sequence of HV-107 (SEQ ID NO: 297). Inyet another embodiment, the anti-PAC1 antibodies or antigen-bindingfragments of the invention comprise a light chain variable regioncomprising the sequence of LV-20 (SEQ ID NO: 71) and a heavy chainvariable region comprising the sequence of HV-110 (SEQ ID NO: 300). Instill another embodiment, the anti-PAC1 antibodies or antigen-bindingfragments of the invention comprise a light chain variable regioncomprising the sequence of LV-26 (SEQ ID NO: 77) and a heavy chainvariable region comprising the sequence of HV-114 (SEQ ID NO: 304).

In some embodiments, the anti-PAC1 antibodies or antigen-bindingfragments thereof comprise a light chain variable region comprising asequence of contiguous amino acids that differs from the sequence of alight chain variable region in Table 1A, i.e. a VL selected from LV-01to LV-36, at only 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15amino acid residues, wherein each such sequence difference isindependently either a deletion, insertion or substitution of one aminoacid, with the deletions, insertions and/or substitutions resulting inno more than 15 amino acid changes relative to the foregoing variabledomain sequences. The light chain variable region in some anti-PAC1antibodies and binding fragments comprises a sequence of amino acidsthat has at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95%, at least 97% or at least 99% sequence identityto the amino acid sequences of SEQ ID NOs: 52 to 87 (i.e. the lightchain variable regions in Table 1A).

In one embodiment, the anti-PAC1 antibody or antigen-binding fragmentthereof comprises a light chain variable region comprising a sequencethat is at least 90% identical to a sequence selected from SEQ ID NOs:54-66. In another embodiment, the anti-PAC1 antibody or antigen-bindingfragment thereof comprises a light chain variable region comprising asequence that is at least 95% identical to a sequence selected from SEQID NOs: 54-66. In yet another embodiment, the anti-PAC1 antibody orantigen-binding fragment thereof comprises a light chain variable regioncomprising a sequence selected from SEQ ID NOs: 54-66. In someembodiments, the anti-PAC1 antibody or antigen-binding fragment thereofcomprises a light chain variable region comprising the sequence of SEQID NO: 54. In other embodiments, the anti-PAC1 antibody orantigen-binding fragment thereof comprises a light chain variable regioncomprising the sequence of SEQ ID NO: 55. In yet other embodiments, theanti-PAC1 antibody or antigen-binding fragment thereof comprises a lightchain variable region comprising the sequence of SEQ ID NO: 62. In stillother embodiments, the anti-PAC1 antibody or antigen-binding fragmentthereof comprises a light chain variable region comprising the sequenceof SEQ ID NO: 63.

In another embodiment, the anti-PAC1 antibody or antigen-bindingfragment thereof comprises a light chain variable region comprising asequence that is at least 90% identical to a sequence selected from SEQID NOs: 68-87. In yet another embodiment, the anti-PAC1 antibody orantigen-binding fragment thereof comprises a light chain variable regioncomprising a sequence that is at least 95% identical to a sequenceselected from SEQ ID NOs: 68-87. In still another embodiment, theanti-PAC1 antibody or antigen-binding fragment thereof comprises a lightchain variable region comprising a sequence selected from SEQ ID NOs:68-87. In certain embodiments, the anti-PAC1 antibody or antigen-bindingfragment thereof comprises a light chain variable region comprising thesequence of SEQ ID NO: 68. In some embodiments, the anti-PAC1 antibodyor antigen-binding fragment thereof comprises a light chain variableregion comprising the sequence of SEQ ID NO: 71. In other embodiments,the anti-PAC1 antibody or antigen-binding fragment thereof comprises alight chain variable region comprising the sequence of SEQ ID NO: 72. Inyet other embodiments, the anti-PAC1 antibody or antigen-bindingfragment thereof comprises a light chain variable region comprising thesequence of SEQ ID NO: 74. In still other embodiments, the anti-PAC1antibody or antigen-binding fragment thereof comprises a light chainvariable region comprising the sequence of SEQ ID NO: 77. In certainembodiments, the anti-PAC1 antibody or antigen-binding fragment thereofcomprises a light chain variable region comprising the sequence of SEQID NO: 78. In other embodiments, the anti-PAC1 antibody orantigen-binding fragment thereof comprises a light chain variable regioncomprising the sequence of SEQ ID NO: 81. In one embodiment, theanti-PAC1 antibody or antigen-binding fragment thereof comprises a lightchain variable region comprising the sequence of SEQ ID NO: 83. Inanother embodiment, the anti-PAC1 antibody or antigen-binding fragmentthereof comprises a light chain variable region comprising the sequenceof SEQ ID NO: 85. In yet another embodiment, the anti-PAC1 antibody orantigen-binding fragment thereof comprises a light chain variable regioncomprising the sequence of SEQ ID NO: 87.

In these and other embodiments, the anti-PAC1 antibodies andantigen-binding fragments thereof comprise a heavy chain variable regioncomprising a sequence of contiguous amino acids that differs from thesequence of a heavy chain variable region in Table 1B, i.e., a VHselected from HV-01 to HV-122, at only 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14 or 15 amino acid residues, wherein each such sequencedifference is independently either a deletion, insertion or substitutionof one amino acid, with the deletions, insertions and/or substitutionsresulting in no more than 15 amino acid changes relative to theforegoing variable domain sequences. The heavy chain variable region insome anti-PAC1 antibodies and antigen-binding fragments comprises asequence of amino acids that has at least 70%, at least 75%, at least80%, at least 85%, at least 90%, at least 95%, at least 97% or at least99% sequence identity to the amino acid sequences of SEQ ID NOs: 191 to312 (i.e. the heavy chain variable regions in Table 1B).

In one embodiment, the anti-PAC1 antibody or antigen-binding fragmentthereof comprises a heavy chain variable region comprising a sequencethat is at least 90% identical to a sequence selected from SEQ ID NOs:191-295. In another embodiment, the anti-PAC1 antibody orantigen-binding fragment thereof comprises a heavy chain variable regioncomprising a sequence that is at least 95% identical to a sequenceselected from SEQ ID NOs: 191-295. In yet another embodiment, theanti-PAC1 antibody or antigen-binding fragment thereof comprises a heavychain variable region comprising a sequence selected from SEQ ID NOs:191-295. In some embodiments, the anti-PAC1 antibody or antigen-bindingfragment thereof comprises a heavy chain variable region comprising thesequence of SEQ ID NO: 194. In other embodiments, the anti-PAC1 antibodyor antigen-binding fragment thereof comprises a heavy chain variableregion comprising the sequence of SEQ ID NO: 203. In yet otherembodiments, the anti-PAC1 antibody or antigen-binding fragment thereofcomprises a heavy chain variable region comprising the sequence of SEQID NO: 214. In still other embodiments, the anti-PAC1 antibody orantigen-binding fragment thereof comprises a heavy chain variable regioncomprising the sequence of SEQ ID NO: 228. In certain embodiments, theanti-PAC1 antibody or antigen-binding fragment thereof comprises a heavychain variable region comprising the sequence of SEQ ID NO: 240. Inother embodiments, the anti-PAC1 antibody or antigen-binding fragmentthereof comprises a heavy chain variable region comprising the sequenceof SEQ ID NO: 274. In one embodiment, the anti-PAC1 antibody orantigen-binding fragment thereof comprises a heavy chain variable regioncomprising the sequence of SEQ ID NO: 282. In another embodiment, theanti-PAC1 antibody or antigen-binding fragment thereof comprises a heavychain variable region comprising the sequence of SEQ ID NO: 283. In yetanother embodiment, the anti-PAC1 antibody or antigen-binding fragmentthereof comprises a heavy chain variable region comprising the sequenceof SEQ ID NO: 284.

In another embodiment, the anti-PAC1 antibody or antigen-bindingfragment thereof comprises a heavy chain variable region comprising asequence that is at least 90% identical to a sequence selected from SEQID NOs: 296-312. In yet another embodiment, the anti-PAC1 antibody orantigen-binding fragment thereof comprises a heavy chain variable regioncomprising a sequence that is at least 95% identical to a sequenceselected from SEQ ID NOs: 296-312. In still another embodiment, theanti-PAC1 antibody or antigen-binding fragment thereof comprises a heavychain variable region comprising a sequence selected from SEQ ID NOs:296-312. In some embodiments, the anti-PAC1 antibody or antigen-bindingfragment thereof comprises a heavy chain variable region comprising thesequence of SEQ ID NO: 296. In other embodiments, the anti-PAC1 antibodyor antigen-binding fragment thereof comprises a heavy chain variableregion comprising the sequence of SEQ ID NO: 297. In yet otherembodiments, the anti-PAC1 antibody or antigen-binding fragment thereofcomprises a heavy chain variable region comprising the sequence of SEQID NO: 300. In still other embodiments, the anti-PAC1 antibody orantigen-binding fragment thereof comprises a heavy chain variable regioncomprising the sequence of SEQ ID NO: 304. In certain embodiments, theanti-PAC1 antibody or antigen-binding fragment thereof comprises a heavychain variable region comprising the sequence of SEQ ID NO: 307. Inother embodiments, the anti-PAC1 antibody or antigen-binding fragmentthereof comprises a heavy chain variable region comprising the sequenceof SEQ ID NO: 310. In one embodiment, the anti-PAC1 antibody orantigen-binding fragment thereof comprises a heavy chain variable regioncomprising the sequence of SEQ ID NO: 312.

The term “identity,” as used herein, refers to a relationship betweenthe sequences of two or more polypeptide molecules or two or morenucleic acid molecules, as determined by aligning and comparing thesequences. “Percent identity,” as used herein, means the percent ofidentical residues between the amino acids or nucleotides in thecompared molecules and is calculated based on the size of the smallestof the molecules being compared. For these calculations, gaps inalignments (if any) must be addressed by a particular mathematical modelor computer program (i.e., an “algorithm”). Methods that can be used tocalculate the identity of the aligned nucleic acids or polypeptidesinclude those described in Computational Molecular Biology, (Lesk, A.M., ed.), 1988, New York: Oxford University Press; BiocomputingInformatics and Genome Projects, (Smith, D. W., ed.), 1993, New York:Academic Press; Computer Analysis of Sequence Data, Part I, (Griffin, A.M., and Griffin, H. G., eds.), 1994, New Jersey: Humana Press; vonHeinje, G., 1987, Sequence Analysis in Molecular Biology, New York:Academic Press; Sequence Analysis Primer, (Gribskov, M. and Devereux,J., eds.), 1991, New York: M. Stockton Press; and Carillo et al., 1988,SIAM J. Applied Math. 48:1073. For example, sequence identity can bedetermined by standard methods that are commonly used to compare thesimilarity in position of the amino acids of two polypeptides. Using acomputer program such as BLAST or FASTA, two polypeptide or twopolynucleotide sequences are aligned for optimal matching of theirrespective residues (either along the full length of one or bothsequences, or along a pre-determined portion of one or both sequences).The programs provide a default opening penalty and a default gappenalty, and a scoring matrix such as PAM 250 (Dayhoff et al., in Atlasof Protein Sequence and Structure, vol. 5, supp. 3, 1978) or BLOSUM62(Henikoff et al., 1992, Proc. Natl. Acad. Sci. U.S.A. 89:10915-10919)can be used in conjunction with the computer program. For example, thepercent identity can then be calculated as: the total number ofidentical matches multiplied by 100 and then divided by the sum of thelength of the longer sequence within the matched span and the number ofgaps introduced into the longer sequences in order to align the twosequences. In calculating percent identity, the sequences being comparedare aligned in a way that gives the largest match between the sequences.

The GCG program package is a computer program that can be used todetermine percent identity, which package includes GAP (Devereux et al.,1984, Nucl. Acid Res. 12:387; Genetics Computer Group, University ofWisconsin, Madison, Wis.). The computer algorithm GAP is used to alignthe two polypeptides or two polynucleotides for which the percentsequence identity is to be determined. The sequences are aligned foroptimal matching of their respective amino acid or nucleotide (the“matched span,” as determined by the algorithm). A gap opening penalty(which is calculated as 3× the average diagonal, wherein the “averagediagonal” is the average of the diagonal of the comparison matrix beingused; the “diagonal” is the score or number assigned to each perfectamino acid match by the particular comparison matrix) and a gapextension penalty (which is usually 1/10 times the gap opening penalty),as well as a comparison matrix such as PAM 250 or BLOSUM 62 are used inconjunction with the algorithm. In certain embodiments, a standardcomparison matrix (see, Dayhoff et al., 1978, Atlas of Protein Sequenceand Structure 5:345-352 for the PAM 250 comparison matrix; Henikoff etal., 1992, Proc. Natl. Acad. Sci. U.S.A. 89:10915-10919 for the BLOSUM62 comparison matrix) is also used by the algorithm.

Recommended parameters for determining percent identity for polypeptidesor nucleotide sequences using the GAP program include the following:

Algorithm: Needleman et al. 1970, J. Mol. Biol. 48:443-453;

Comparison matrix: BLOSUM 62 from Henikoff et al., 1992, supra;

Gap Penalty: 12 (but with no penalty for end gaps)

Gap Length Penalty: 4

Threshold of Similarity: 0

Certain alignment schemes for aligning two amino acid sequences mayresult in matching of only a short region of the two sequences, and thissmall aligned region may have very high sequence identity even thoughthere is no significant relationship between the two full-lengthsequences. Accordingly, the selected alignment method (GAP program) canbe adjusted if so desired to result in an alignment that spans at least50 contiguous amino acids of the target polypeptide.

The anti-PAC1 antibodies of the invention can comprise anyimmunoglobulin constant region. The term “constant region,” usedinterchangeably herein with “constant domain” refers to all domains ofan antibody other than the variable region. The constant region is notinvolved directly in binding of an antigen, but exhibits variouseffector functions. As described above, antibodies are divided intoparticular isotypes (IgA, IgD, IgE, IgG, and IgM) and subtypes (IgG1,IgG2, IgG3, IgG4, IgA1 IgA2) depending on the amino acid sequence of theconstant region of their heavy chains. The light chain constant regioncan be, for example, a kappa- or lambda-type light chain constantregion, e.g., a human kappa- or lambda-type light chain constant region,which are found in all five antibody isotypes. Examples of humanimmunoglobulin light chain constant region sequences are shown in thefollowing table.

TABLE 2 Exemplary Human Immunoglobulin Light Chain Constant Regions SEQID Designation NO: CL Domain Amino Acid Sequence Human 313GQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKA lambda v1DGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSC QVTHEGSTVEKTVAPTECS Human314 GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKA lambda v2DSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQ VTHEGSTVEKTVAPTECS Human315 QPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKAD lambda v3SSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQV THEGSTVEKTVAPTECS Human 316GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKA lambda v4DSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQ VTHEGSTVEKTVAPTECS Human317 GQPKAAPSVTLFPPSSEELQANKATLVCLVSDFYPGAVTVAWK lambda v5ADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYS CRVTHEGSTVEKTVAPAECS Human318 TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN kappa v1ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV THQGLSSPVTKSFNRGEC Human319 RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD kappa v2NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC

The heavy chain constant region of the anti-PAC1 antibodies of theinvention can be, for example, an alpha-, delta-, epsilon-, gamma-, ormu-type heavy chain constant region, e.g., a human alpha-, delta-,epsilon-, gamma-, or mu-type heavy chain constant region. In someembodiments, the anti-PAC1 antibodies comprise a heavy chain constantregion from an IgG1, IgG2, IgG3, or IgG4 immunoglobulin, such as a humanIgG1, IgG2, IgG3, or IgG4 immunoglobulin. In one embodiment, theanti-PAC1 antibody comprises a heavy chain constant region from a humanIgG1 immunoglobulin. In such embodiments, the human IgG1 immunoglobulinconstant region may comprise one or more mutations to preventglycosylation of the antibody as described in more detail herein. Inanother embodiment, the anti-PAC1 antibody comprises a heavy chainconstant region from a human IgG2 immunoglobulin. In yet anotherembodiment, the anti-PAC1 antibody comprises a heavy chain constantregion from a human IgG4 immunoglobulin. Examples of human IgG1, IgG2,and IgG4 heavy chain constant region sequences are shown below in Table3.

TABLE 3 Exemplary Human Immunoglobulin Heavy Chain Constant Regions SEQID Ig isotype NO: Heavy Chain Constant Region Amino Acid SequenceHuman IgG1z 320 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Human IgG1za 321ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Human IgG1f 322ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Human IgG1fa 323ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Human IgG1z 324ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN aglycosylatedSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV v1NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Human IgG1z 325ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN aglycosylatedSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV v2NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Human IgG2 326ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Human IgG4 327ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Each of the light chain variable regions disclosed in Table 1A and eachof the heavy chain variable regions disclosed in Table 1B may beattached to the above light chain constant regions (Table 2) and heavychain constant regions (Table 3) to form complete antibody light andheavy chains, respectively. Further, each of the so generated heavy andlight chain sequences may be combined to form a complete antibodystructure. It should be understood that the heavy chain and light chainvariable regions provided herein can also be attached to other constantdomains having different sequences than the exemplary sequences listedabove.

The anti-PAC1 antibodies or antigen-binding fragments of the inventioncan be any of the anti-PAC1 antibodies or antigen-binding fragmentsdisclosed herein. For example, in certain embodiments, the anti-PAC1antibody is an anti-PAC1 antibody selected from any of the antibodieslisted in Tables 9, 10, 12, 13, 14, 19, and 20. In some embodiments, theanti-PAC1 antibodies comprise a light chain variable region and/or aheavy chain variable region having one or more of the amino acidsubstitutions set forth in Tables 9, 10, 12, 13, 19, or 20. Forinstance, in one embodiment, the anti-PAC1 antibody comprises a lightchain variable region comprising the sequence of SEQ ID NO: 52 with amutation at one or more amino acid positions 27, 28, 30, 31, 32, and/or93. In certain embodiments, the mutation is selected from Q27K, Q27R,Q27H, S28A, G30M, G30W, R31Q, R31L, R31H, R31W, R31Y, S32A, S32N, S32L,R93F, R93M, R93Y, or combinations thereof. In these and otherembodiments, the anti-PAC1 antibody comprises a heavy chain variableregion comprising the sequence of SEQ ID NO: 191 with a mutation at oneor more amino acid positions 31, 32, 49, 52, 53, 54, 56, 57, 62, 70,102, 103, and/or 104. In some embodiments, the mutation is selected fromR31F, R31H, R31Y, R31M, R31K, F32Y, A49G, S52N, S52T, Y53F, Y53H, Y53S,D54I, D54L, D54N, D54R, D54Q, D54Y, D54F, D54M, D54S, D54T, G56Q, G56N,G56R, G56H, G56A, G56S, G56T, G56D, N57A, N57F, N57G, N57S, N57Q, N57L,N57T, E62R, I70V, I70L, I70M, V102P, V102L, V102I, V102F, V102M, L103M,T104S, or combinations thereof.

In another embodiment, the anti-PAC1 antibody comprises a light chainvariable region comprising the sequence of SEQ ID NO: 67 with a mutationat one or more amino acid positions 28, 30, 31, 34, 49, 50, 51, 52, 53,91, 92, 93, 94, and/or 96. The mutation can be selected from S28Y, S28T,S28K, S28P, S28Q, S28R, S28M, S30A, S30V, R31Q, N34V, N34S, Y49F, A50V,A50G, A51G, A515, S52Q, S52H, S52N, S52Y, S52R, S52L, S53I, S53Y, S53N,S53M, S53H, S53R, S91A, Y921, S93G, S93Q, S93I, S93N, S93M, P94E, P94M,P94N, P94Q, P94A, P94T, P941, F96Y, or combinations thereof. In theseand other embodiments, the anti-PAC1 antibody comprises a heavy chainvariable region comprising the sequence of SEQ ID NO: 296 with amutation at one or more amino acid positions 31, 32, 33, 57, 58, 60,103, 105, 106, 107, and/or 110. In some embodiments, the mutation isselected from S31N, N32R, N32K, N32H, S33L, S33Q, S33Y, S33V, S33D,S57G, K58Q, S60K, T103M, T103Q, T103R, T103V, K105N, K105E, K105D,K105I, K105A, K1055, K105Q, Q106G, Q106E, L107D, L107N, L110M, L110F, orcombinations thereof.

In certain embodiments, the anti-PAC1 antibody or antigen-bindingfragment of the invention is selected from antibodies 420653, 420845,420943, 421873, 420889, 421091, 421051, 480711, 480706, 480713, 448730,448195, 448788, 448901, 448689, 448202, 452128, 448924, 3574, and 3575or antigen-binding fragments thereof, the variable region and CDRsequences of which are set forth in Tables 1A and 1B. In someembodiments, the anti-PAC1 antibody is an antibody selected from 420653,420845, 420943, 421873, 420889, 421091, 421051, 480711, 480706, and480713 antibodies. In other embodiments, the anti-PAC1 antibody is anantibody selected from 448730, 448195, 448788, 448901, 448689, 448202,452128, 448924, 3574, and 3575 antibodies. Full-length light chain andfull-length heavy chain sequences of these exemplary human anti-PAC1antibodies are set forth below in Tables 4A and 4B, respectively.

TABLE 4A Exemplary Anti-PAC1 Antibody Light Chain Sequences Antibody LCID. Group Light Chain Amino Acid SequenceLight Chain Nucleic Acid Sequence 29G4 variants 29G4v10 LC-01EIVLTQSPATLSLSPGERATLSCRA GAGATCGTACTTACTCAGTCACCCGCCACASQSVGRSLHWYQQKPGQAPRLLI TTGTCCCTGAGCCCGGGTGAACGGGCGACCKYASQSLSGIPARFSGSGSGTDFT CTCAGCTGCCGAGCATCCCAGTCCGTCGGALTISSLEPEDFAVYYCHQSSRLPFT CGATCATTGCACTGGTACCAACAAAAACCGFGPGTKVDIKRTVAAPSVFIFPPSD GGCCAGGCCCCCAGACTTCTGATCAAGTATEQLKSGTASVVCLLNNFYPREAK GCGTCACAGAGCTTGTCGGGTATTCCCGCTCVQWKVDNALQSGNSQESVTEQD GCTTTTCGGGGTCGGGATCCGGGACAGATTSKDSTYSLSSTLTLSKADYEKHKV TCACGCTCACAATCTCCTCGCTGGAACCCGYACEVTHQGLSSPVTKSFNRGEC AGGACTTCGCGGTCTACTATTGTCATCAGTC (SEQ ID NO: 504)ATCGAGGTTGCCTTTCACGTTTGGACCAGG GACCAAGGTGGACATTAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCT GATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCA GAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAG AGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCT GAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCC TGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 537) 29G4v22 LC-02 DIQLTQSPSFLSASVGDRVTITCRAGATATCCAGCTCACTCAATCGCCATCATTTC SQSIGRSLHWYQQKPGKAPKLLIKTCTCCGCTTCGGTAGGCGACCGGGTCACGA YASQSLSGVPSRFSGSGSGTEFTLTCACATGCAGGGCGTCGCAAAGCATTGGGA TISSLQPEDFATYYCHQSSRLPFTFGGTCGTTGCATTGGTATCAGCAGAAACCCG GPGTKVDIKRTVAAPSVFIFPPSDEGAAAGGCCCCGAAACTTCTGATCAAATACG QLKSGTASVVCLLNNFYPREAKVCATCACAAAGCTTGAGCGGTGTGCCGTCGC QWKVDNALQSGNSQESVTEQDSGCTTCTCCGGTTCCGGAAGCGGAACGGAAT KDSTYSLSSTLTLSKADYEKHKVTCACGCTTACAATCTCCTCACTGCAGCCCGA YACEVTHQGLSSPVTKSFNRGECGGATTTCGCGACCTATTACTGTCACCAGTCA (SEQ ID NO: 505)TCCAGACTCCCGTTTACTTTTGGCCCTGGGA CCAAGGTGGACATTAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGA TGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAG AGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGT GTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAG CAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAG CTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 538) iPS: 420653 LC-03 EIVLTQSPATLSLSPGERATLSCRAGAGATCGTACTTACTCAGTCACCCGCCACA SKSVGRSLHWYQQKPGQAPRLLITTGTCCCTGAGCCCGGGTGAACGGGCGACC KYASQSLSGIPARFSGSGSGTDFTCTCAGCTGCCGAGCATCCAAGTCCGTCGGA LTISSLEPEDFAVYYCHQSSRLPFTCGATCATTGCACTGGTACCAACAAAAACCG FGPGTKVDIKRTVAAPSVFIFPPSDGGCCAGGCCCCCAGACTTCTGATCAAGTAT EQLKSGTASVVCLLNNFYPREAKGCGTCACAGAGCTTGTCGGGTATTCCCGCTC VQWKVDNALQSGNSQESVTEQDGCTTTTCGGGGTCGGGATCCGGGACAGATT SKDSTYSLSSTLTLSKADYEKHKVTCACGCTCACAATCTCCTCGCTGGAACCCG YACEVTHQGLSSPVTKSFNRGECAGGACTTCGCGGTCTACTATTGTCATCAGTC (SEQ ID NO: 506)ATCGAGGTTGCCTTTCACGTTTGGACCAGG GACCAAGGTGGACATTAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCT GATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCA GAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAG AGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCT GAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCC TGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 539) iPS: 420845 LC-03 EIVLTQSPATLSLSPGERATLSCRAGAGATCGTACTTACTCAGTCACCCGCCACA SKSVGRSLHWYQQKPGQAPRLLITTGTCCCTGAGCCCGGGTGAACGGGCGACC KYASQSLSGIPARFSGSGSGTDFTCTCAGCTGCCGAGCATCCAAGTCCGTCGGA LTISSLEPEDFAVYYCHQSSRLPFTCGATCATTGCACTGGTACCAACAAAAACCG FGPGTKVDIKRTVAAPSVFIFPPSDGGCCAGGCCCCCAGACTTCTGATCAAGTAT EQLKSGTASVVCLLNNFYPREAKGCGTCACAGAGCTTGTCGGGTATTCCCGCTC VQWKVDNALQSGNSQESVTEQDGCTTTTCGGGGTCGGGATCCGGGACAGATT SKDSTYSLSSTLTLSKADYEKHKVTCACGCTCACAATCTCCTCGCTGGAACCCG YACEVTHQGLSSPVTKSFNRGECAGGACTTCGCGGTCTACTATTGTCATCAGTC (SEQ ID NO: 506)ATCGAGGTTGCCTTTCACGTTTGGACCAGG GACCAAGGTGGACATTAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCT GATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCA GAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAG AGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCT GAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCC TGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 539) iPS: 420943 LC-01 EIVLTQSPATLSLSPGERATLSCRAGAGATCGTACTTACTCAGTCACCCGCCACA SQSVGRSLHWYQQKPGQAPRLLITTGTCCCTGAGCCCGGGTGAACGGGCGACC KYASQSLSGIPARFSGSGSGTDFTCTCAGCTGCCGAGCATCCCAGTCCGTCGGA LTISSLEPEDFAVYYCHQSSRLPFTCGATCATTGCACTGGTACCAACAAAAACCG FGPGTKVDIKRTVAAPSVFIFPPSDGGCCAGGCCCCCAGACTTCTGATCAAGTAT EQLKSGTASVVCLLNNFYPREAKGCGTCACAGAGCTTGTCGGGTATTCCCGCTC VQWKVDNALQSGNSQESVTEQDGCTTTTCGGGGTCGGGATCCGGGACAGATT SKDSTYSLSSTLTLSKADYEKHKVTCACGCTCACAATCTCCTCGCTGGAACCCG YACEVTHQGLSSPVTKSFNRGECAGGACTTCGCGGTCTACTATTGTCATCAGTC (SEQ ID NO: 504)ATCGAGGTTGCCTTTCACGTTTGGACCAGG GACCAAGGTGGACATTAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCT GATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCA GAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAG AGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCT GAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCC TGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 537) iPS: 421873 LC-01 EIVLTQSPATLSLSPGERATLSCRAGAGATCGTACTTACTCAGTCACCCGCCACA SQSVGRSLHWYQQKPGQAPRLLITTGTCCCTGAGCCCGGGTGAACGGGCGACC KYASQSLSGIPARFSGSGSGTDFTCTCAGCTGCCGAGCATCCCAGTCCGTCGGA LTISSLEPEDFAVYYCHQSSRLPFTCGATCATTGCACTGGTACCAACAAAAACCG FGPGTKVDIKRTVAAPSVFIFPPSDGGCCAGGCCCCCAGACTTCTGATCAAGTAT EQLKSGTASVVCLLNNFYPREAKGCGTCACAGAGCTTGTCGGGTATTCCCGCTC VQWKVDNALQSGNSQESVTEQDGCTTTTCGGGGTCGGGATCCGGGACAGATT SKDSTYSLSSTLTLSKADYEKHKVTCACGCTCACAATCTCCTCGCTGGAACCCG YACEVTHQGLSSPVTKSFNRGECAGGACTTCGCGGTCTACTATTGTCATCAGTC (SEQ ID NO: 504)ATCGAGGTTGCCTTTCACGTTTGGACCAGG GACCAAGGTGGACATTAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCT GATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCA GAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAG AGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCT GAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCC TGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 537) iPS: 420889 LC-03 EIVLTQSPATLSLSPGERATLSCRAGAGATCGTACTTACTCAGTCACCCGCCACA SKSVGRSLHWYQQKPGQAPRLLITTGTCCCTGAGCCCGGGTGAACGGGCGACC KYASQSLSGIPARFSGSGSGTDFTCTCAGCTGCCGAGCATCCAAGTCCGTCGGA LTISSLEPEDFAVYYCHQSSRLPFTCGATCATTGCACTGGTACCAACAAAAACCG FGPGTKVDIKRTVAAPSVFIFPPSDGGCCAGGCCCCCAGACTTCTGATCAAGTAT EQLKSGTASVVCLLNNFYPREAKGCGTCACAGAGCTTGTCGGGTATTCCCGCTC VQWKVDNALQSGNSQESVTEQDGCTTTTCGGGGTCGGGATCCGGGACAGATT SKDSTYSLSSTLTLSKADYEKHKVTCACGCTCACAATCTCCTCGCTGGAACCCG YACEVTHQGLSSPVTKSFNRGECAGGACTTCGCGGTCTACTATTGTCATCAGTC (SEQ ID NO: 506)ATCGAGGTTGCCTTTCACGTTTGGACCAGG GACCAAGGTGGACATTAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCT GATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCA GAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAG AGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCT GAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCC TGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 539) iPS: 421091 LC-01 EIVLTQSPATLSLSPGERATLSCRAGAGATCGTACTTACTCAGTCACCCGCCACA SQSVGRSLHWYQQKPGQAPRLLITTGTCCCTGAGCCCGGGTGAACGGGCGACC KYASQSLSGIPARFSGSGSGTDFTCTCAGCTGCCGAGCATCCCAGTCCGTCGGA LTISSLEPEDFAVYYCHQSSRLPFTCGATCATTGCACTGGTACCAACAAAAACCG FGPGTKVDIKRTVAAPSVFIFPPSDGGCCAGGCCCCCAGACTTCTGATCAAGTAT EQLKSGTASVVCLLNNFYPREAKGCGTCACAGAGCTTGTCGGGTATTCCCGCTC VQWKVDNALQSGNSQESVTEQDGCTTTTCGGGGTCGGGATCCGGGACAGATT SKDSTYSLSSTLTLSKADYEKHKVTCACGCTCACAATCTCCTCGCTGGAACCCG YACEVTHQGLSSPVTKSFNRGECAGGACTTCGCGGTCTACTATTGTCATCAGTC (SEQ ID NO: 504)ATCGAGGTTGCCTTTCACGTTTGGACCAGG GACCAAGGTGGACATTAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCT GATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCA GAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAG AGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCT GAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCC TGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 537) iPS: 421051 LC-03 EIVLTQSPATLSLSPGERATLSCRAGAGATCGTACTTACTCAGTCACCCGCCACA SKSVGRSLHWYQQKPGQAPRLLITTGTCCCTGAGCCCGGGTGAACGGGCGACC KYASQSLSGIPARFSGSGSGTDFTCTCAGCTGCCGAGCATCCAAGTCCGTCGGA LTISSLEPEDFAVYYCHQSSRLPFTCGATCATTGCACTGGTACCAACAAAAACCG FGPGTKVDIKRTVAAPSVFIFPPSDGGCCAGGCCCCCAGACTTCTGATCAAGTAT EQLKSGTASVVCLLNNFYPREAKGCGTCACAGAGCTTGTCGGGTATTCCCGCTC VQWKVDNALQSGNSQESVTEQDGCTTTTCGGGGTCGGGATCCGGGACAGATT SKDSTYSLSSTLTLSKADYEKHKVTCACGCTCACAATCTCCTCGCTGGAACCCG YACEVTHQGLSSPVTKSFNRGECAGGACTTCGCGGTCTACTATTGTCATCAGTC (SEQ ID NO: 506)ATCGAGGTTGCCTTTCACGTTTGGACCAGG GACCAAGGTGGACATTAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCT GATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCA GAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAG AGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCT GAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCC TGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 539) iPS: 480711 LC-04 EIVLTQSPATLSLSPGERATLSCRAGAGATCGTACTTACTCAGTCACCCGCCACA SKSVGWSLHWYQQKPGQAPRLLITTGTCCCTGAGCCCGGGTGAACGGGCGACC KYASQSLSGIPARFSGSGSGTDFTCTCAGCTGCCGAGCATCCAAATCCGTCGGG LTISSLEPEDFAVYYCHQSSRLPFTTGGAGCTTGCACTGGTACCAACAAAAACCG FGPGTKVDIKRTVAAPSVFIFPPSDGGCCAGGCCCCCAGACTTCTGATCAAGTAT EQLKSGTASVVCLLNNFYPREAKGCGTCACAGAGCTTGTCGGGTATTCCCGCTC VQWKVDNALQSGNSQESVTEQDGCTTTTCGGGGTCGGGATCCGGGACAGATT SKDSTYSLSSTLTLSKADYEKHKVTCACGCTCACAATCTCCTCGCTGGAACCCG YACEVTHQGLSSPVTKSFNRGECAGGACTTCGCGGTCTACTATTGTCATCAGTC (SEQ ID NO: 507)ATCGAGGTTGCCTTTCACGTTTGGACCAGG GACCAAGGTGGACATTAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCT GATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCA GAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAG AGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCT GAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCC TGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 540) iPS: 480706 LC-04 EIVLTQSPATLSLSPGERATLSCRAGAGATCGTACTTACTCAGTCACCCGCCACA SKSVGWSLHWYQQKPGQAPRLLITTGTCCCTGAGCCCGGGTGAACGGGCGACC KYASQSLSGIPARFSGSGSGTDFTCTCAGCTGCCGAGCATCCAAATCCGTCGGG LTISSLEPEDFAVYYCHQSSRLPFTTGGAGCTTGCACTGGTACCAACAAAAACCG FGPGTKVDIKRTVAAPSVFIFPPSDGGCCAGGCCCCCAGACTTCTGATCAAGTAT EQLKSGTASVVCLLNNFYPREAKGCGTCACAGAGCTTGTCGGGTATTCCCGCTC VQWKVDNALQSGNSQESVTEQDGCTTTTCGGGGTCGGGATCCGGGACAGATT SKDSTYSLSSTLTLSKADYEKHKVTCACGCTCACAATCTCCTCGCTGGAACCCG YACEVTHQGLSSPVTKSFNRGECAGGACTTCGCGGTCTACTATTGTCATCAGTC (SEQ ID NO: 507)ATCGAGGTTGCCTTTCACGTTTGGACCAGG GACCAAGGTGGACATTAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCT GATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCA GAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAG AGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCT GAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCC TGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 540) iPS: 480713 LC-05 EIVLTQSPATLSLSPGERATLSCRAGAGATCGTACTTACTCAGTCACCCGCCACA SKSVGYSLHWYQQKPGQAPRLLITTGTCCCTGAGCCCGGGTGAACGGGCGACC KYASQSLSGIPARFSGSGSGTDFTCTCAGCTGCCGAGCATCCAAATCCGTCGGG LTISSLEPEDFAVYYCHQSSRLPFTTACAGCTTGCACTGGTACCAACAAAAACCG FGPGTKVDIKRTVAAPSVFIFPPSDGGCCAGGCCCCCAGACTTCTGATCAAGTAT EQLKSGTASVVCLLNNFYPREAKGCGTCACAGAGCTTGTCGGGTATTCCCGCTC VQWKVDNALQSGNSQESVTEQDGCTTTTCGGGGTCGGGATCCGGGACAGATT SKDSTYSLSSTLTLSKADYEKHKVTCACGCTCACAATCTCCTCGCTGGAACCCG YACEVTHQGLSSPVTKSFNRGECAGGACTTCGCGGTCTACTATTGTCATCAGTC (SEQ ID NO: 508)ATCGAGGTTGCCTTTCACGTTTGGACCAGG GACCAAGGTGGACATTAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCT GATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCA GAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAG AGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCT GAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCC TGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 541) 19H8 variants 19H8 LC-06DIQMTQSPSSLSASVGDRITITCRA GACATCCAGATGACCCAGTCTCCATCCTCCCSQSISRYLNWYQQKPGKAPKLLIY TGTCTGCATCTGTAGGAGACAGAATCACCAAASSLQSGIPSRFSGSGSGTDFTLT TCACTTGCCGGGCAAGTCAGAGCATTAGCAINSLQPEDFATYFCQQSYSPPFTFG GGTATTTAAATTGGTATCAACAGAAACCAGPGTKVDIKRTVAAPSVFIFPPSDEQ GGAAAGCCCCTAAACTCCTGATCTATGCTGLKSGTASVVCLLNNFYPREAKVQ CATCCAGTTTGCAAAGTGGGATCCCATCAAWKVDNALQSGNSQESVTEQDSK GGTTCAGCGGCAGTGGATCTGGGACAGATTDSTYSLSSTLTLSKADYEKHKVY TCACTCTCACCATCAACAGTCTGCAACCTGAACEVTHQGLSSPVTKSFNRGEC AGATTTTGCAACTTACTTCTGTCAACAGAGT (SEQ ID NO: 509)TACAGTCCCCCATTCACTTTCGGCCCTGGGA CCAAAGTGGATATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGA TGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAG AGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGT GTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAG CAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAG CTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 542) iPS: 448730 LC-07 DIQMTQSPSSLSASVGDRITITCRAGACATCCAGATGACCCAGTCTCCATCCTCCC SQMIARYLNWYQQKPGKAPKLLITGTCTGCATCTGTAGGAGACAGAATCACCA YASYNLQSGIPSRFSGSGSGTDFTTCACTTGCCGGGCAAGTCAGATGATTGCTC LTINSLQPEDFATYFCQQAIINPYTGTTACTTAAACTGGTATCAACAGAAACCAG FGPGTKVDIKRTVAAPSVFIFPPSDGGAAAGCCCCTAAACTCCTGATCTACGCTT EQLKSGTASVVCLLNNFYPREAKCTTACAACTTGCAAAGTGGGATCCCATCAA VQWKVDNALQSGNSQESVTEQDGGTTCAGCGGCAGTGGATCTGGGACAGATT SKDSTYSLSSTLTLSKADYEKHKVTCACTCTCACCATCAACAGTCTGCAACCTGA YACEVTHQGLSSPVTKSFNRGECAGATTTTGCAACTTACTTCTGTCAACAGGCT (SEQ ID NO: 510)ATCATCAACCCATACACTTTCGGCCCTGGG ACCAAAGTGGATATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTG ATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAG AGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGA GTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTG AGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCT GAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 543) iPS: 448195 LC-08 DIQMTQSPSSLSASVGDRITITCRAGACATCCAGATGACCCAGTCTCCATCCTCCC SQKIARYLVWYQQKPGKAPKLLITGTCTGCATCTGTAGGAGACAGAATCACCA YAANMLQSGIPSRFSGSGSGTDFTTCACTTGCCGGGCAAGTCAGAAAATTGCTC LTINSLQPEDFATYFCQQSIQQPYTGTTACTTAGTTTGGTATCAACAGAAACCAG FGPGTKVDIKRTVAAPSVFIFPPSDGGAAAGCCCCTAAACTCCTGATCTACGCTG EQLKSGTASVVCLLNNFYPREAKCTAACATGTTGCAAAGTGGGATCCCATCAA VQWKVDNALQSGNSQESVTEQDGGTTCAGCGGCAGTGGATCTGGGACAGATT SKDSTYSLSSTLTLSKADYEKHKVTCACTCTCACCATCAACAGTCTGCAACCTGA YACEVTHQGLSSPVTKSFNRGECAGATTTTGCAACTTACTTCTGTCAACAGTCT (SEQ ID NO: 511)ATCCAGCAGCCATACACTTTCGGCCCTGGG ACCAAAGTGGATATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTG ATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAG AGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGA GTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTG AGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCT GAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 544) iPS: 448788 LC-09 DIQMTQSPSSLSASVGDRITITCRAGACATCCAGATGACCCAGTCTCCATCCTCCC SQSISRYLNWYQQKPGKAPKLLIYTGTCTGCATCTGTAGGAGACAGAATCACCA AGRILQSGIPSRFSGSGSGTDFTLTTCACTTGCCGGGCAAGTCAGAGCATTAGCA INSLQPEDFATYFCQQAIINPYTFGGGTATTTAAATTGGTATCAACAGAAACCAG PGTKVDIKRTVAAPSVFIFPPSDEQGGAAAGCCCCTAAACTCCTGATCTACGCTG LKSGTASVVCLLNNFYPREAKVQGTCGTATCTTGCAAAGTGGGATCCCATCAA WKVDNALQSGNSQESVTEQDSKGGTTCAGCGGCAGTGGATCTGGGACAGATT DSTYSLSSTLTLSKADYEKHKVYTCACTCTCACCATCAACAGTCTGCAACCTGA ACEVTHQGLSSPVTKSFNRGECAGATTTTGCAACTTACTTCTGTCAACAGGCT (SEQ ID NO: 512)ATCATCAACCCATACACTTTCGGCCCTGGG ACCAAAGTGGATATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTG ATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAG AGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGA GTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTG AGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCT GAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 545) iPS: 448901 LC-10 DIQMTQSPSSLSASVGDRITITCRAGACATCCAGATGACCCAGTCTCCATCCTCCC SQSISRYLNWYQQKPGKAPKLLIYTGTCTGCATCTGTAGGAGACAGAATCACCA ASYNLQSGIPSRFSGSGSGTDFTLTTCACTTGCCGGGCAAGTCAGAGCATTAGCA INSLQPEDFATYFCQQSIQQPYTFGGTATTTAAATTGGTATCAACAGAAACCAG GPGTKVDIKRTVAAPSVFIFPPSDEGGAAAGCCCCTAAACTCCTGATCTACGCTT QLKSGTASVVCLLNNFYPREAKVCTTACAACTTGCAAAGTGGGATCCCATCAA QWKVDNALQSGNSQESVTEQDSGGTTCAGCGGCAGTGGATCTGGGACAGATT KDSTYSLSSTLTLSKADYEKHKVTCACTCTCACCATCAACAGTCTGCAACCTGA YACEVTHQGLSSPVTKSFNRGECAGATTTTGCAACTTACTTCTGTCAACAGTCT (SEQ ID NO: 513)ATCCAGCAGCCATACACTTTCGGCCCTGGG ACCAAAGTGGATATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTG ATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAG AGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGA GTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTG AGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCT GAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 546) iPS: 448689 LC-11 DIQMTQSPSSLSASVGDRITITCRAGACATCCAGATGACCCAGTCTCCATCCTCCC SQYIVRYLNWYQQKPGKAPKLLITGTCTGCATCTGTAGGAGACAGAATCACCA YASYNLQSGIPSRFSGSGSGTDFTTCACTTGCCGGGCAAGTCAGTACATTGTTCG LTINSLQPEDFATYFCQQAIMAPYTTACTTAAACTGGTATCAACAGAAACCAGG TFGPGTKVDIKRTVAAPSVFIFPPSGAAAGCCCCTAAACTCCTGATCTACGCTTCT DEQLKSGTASVVCLLNNFYPREATACAACTTGCAAAGTGGGATCCCATCAAGG KVQWKVDNALQSGNSQESVIEQTTCAGCGGCAGTGGATCTGGGACAGATTTC DSKDSTYSLSSTLTLSKADYEKHKACTCTCACCATCAACAGTCTGCAACCTGAA VYACEVTHQGLSSPVTKSFNRGEGATTTTGCAACTTACTTCTGTCAACAGGCTA C (SEQ ID NO: 514)TCATGGCTCCATACACTTTCGGCCCTGGGAC CAAAGTGGATATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGA TGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAG AGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGT GTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAG CAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAG CTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 547) iPS: 448202 LC-12 DIQMTQSPSSLSASVGDRITITCRAGACATCCAGATGACCCAGTCTCCATCCTCCC SQSISRYLNWYQQKPGKAPKLLIFTGTCTGCATCTGTAGGAGACAGAATCACCA AGQRLQSGIPSRFSGSGSGTDFTLTCACTTGCCGGGCAAGTCAGAGCATTAGCA TINSLQPEDFATYFCQQAIGMPYTGGTATTTAAATTGGTATCAACAGAAACCAG FGPGTKVDIKRTVAAPSVFIFPPSDGGAAAGCCCCTAAACTCCTGATCTTCGCTG EQLKSGTASVVCLLNNFYPREAKGTCAGCGTTTGCAAAGTGGGATCCCATCAA VQWKVDNALQSGNSQESVTEQDGGTTCAGCGGCAGTGGATCTGGGACAGATT SKDSTYSLSSTLTLSKADYEKHKVTCACTCTCACCATCAACAGTCTGCAACCTGA YACEVTHQGLSSPVTKSFNRGECAGATTTTGCAACTTACTTCTGTCAACAGGCT (SEQ ID NO: 515)ATCGGTATGCCATACACTTTCGGCCCTGGG ACCAAAGTGGATATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTG ATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAG AGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGA GTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTG AGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCT GAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 548) iPS: 452128 LC-13 DIQMTQSPSSLSASVGDRITITCRAGACATCCAGATGACCCAGTCTCCATCCTCCC SQYIVRYLNWYQQKPGKAPKLLITGTCTGCATCTGTAGGAGACAGAATCACCA YAANMLQSGIPSRFSGSGSGTDFTTCACTTGCCGGGCAAGTCAGTACATTGTTCG LTINSLQPEDFATYFCQQAINQPYTTACTTAAACTGGTATCAACAGAAACCAGG TFGPGTKVDIKRTVAAPSVFIFPPSGAAAGCCCCTAAACTCCTGATCTACGCTGC DEQLKSGTASVVCLLNNFYPREATAACATGTTGCAAAGTGGGATCCCATCAAG KVQWKVDNALQSGNSQESVTEQGTTCAGCGGCAGTGGATCTGGGACAGATTT DSKDSTYSLSSTLTLSKADYEKHKCACTCTCACCATCAACAGTCTGCAACCTGA VYACEVTHQGLSSPVTKSFNRGEAGATTTTGCAACTTACTTCTGTCAACAGGCT C (SEQ ID NO: 516)ATCAACCAGCCATACACTTTCGGCCCTGGG ACCAAAGTGGATATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTG ATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAG AGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGA GTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTG AGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCT GAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 549) iPS: 448924 LC-14 DIQMTQSPSSLSASVGDRITITCRAGACATCCAGATGACCCAGTCTCCATCCTCCC SQPISRYLSWYQQKPGKAPKLLIFTGTCTGCATCTGTAGGAGACAGAATCACCA AGQRLQSGIPSRFSGSGSGTDFTLTCACTTGCCGGGCAAGTCAGCCGATTTCTCG TINSLQPEDFATYFCQQAISIPYTFTTACTTATCTTGGTATCAACAGAAACCAGG GPGTKVDIKRTVAAPSVFIFPPSDEGAAAGCCCCTAAACTCCTGATCTTCGCTGGT QLKSGTASVVCLLNNFYPREAKVCAGCGTTTGCAAAGTGGGATCCCATCAAGG QWKVDNALQSGNSQESVTEQDSTTCAGCGGCAGTGGATCTGGGACAGATTTC KDSTYSLSSTLTLSKADYEKHKVACTCTCACCATCAACAGTCTGCAACCTGAA YACEVTHQGLSSPVTKSFNRGECGATTTTGCAACTTACTTCTGTCAACAGGCTA (SEQ ID NO: 517)TCTCTATCCCATACACTTTCGGCCCTGGGAC CAAAGTGGATATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGA TGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAG AGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGT GTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAG CAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAG CTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 550) 3574 LC-06 DIQMTQSPSSLSASVGDRITITCRAGACATCCAGATGACCCAGTCTCCATCCTCCC SQSISRYLNWYQQKPGKAPKLLIYTGTCTGCATCTGTAGGAGACAGAATCACCA AASSLQSGIPSRFSGSGSGTDFTLTTCACTTGCCGGGCAAGTCAGAGCATTAGCA INSLQPEDFATYFCQQSYSPPFTFGGGTATTTAAATTGGTATCAACAGAAACCAG PGTKVDIKRTVAAPSVFIFPPSDEQGGAAAGCCCCTAAACTCCTGATCTATGCTG LKSGTASVVCLLNNFYPREAKVQCATCCAGTTTGCAAAGTGGGATCCCATCAA WKVDNALQSGNSQESVTEQDSKGGTTCAGCGGCAGTGGATCTGGGACAGATT DSTYSLSSTLTLSKADYEKHKVYTCACTCTCACCATCAACAGTCTGCAACCTGA ACEVTHQGLSSPVTKSFNRGECAGATTTTGCAACTTACTTCTGTCAACAGAGT (SEQ ID NO: 509)TACAGTCCCCCATTCACTTTCGGCCCTGGGA CCAAAGTGGATATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGA TGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAG AGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGT GTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAG CAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAG CTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 542) 3575 LC-15 DIQMTQSPSSLSASVGDRITITCRAGACATCCAGATGACCCAGTCTCCATCCTCCC SQQIARYLNWYQQKPGKAPKLLITGTCTGCATCTGTAGGAGACAGAATCACCA YASYNLQSGIPSRFSGSGSGTDFTTCACTTGCCGGGCAAGTCAGCAGATTGCTC LTINSLQPEDFATYFCQQAIIQPYTGTTACTTAAACTGGTATCAACAGAAACCAG FGPGTKVDIKRTVAAPSVFIFPPSDGGAAAGCCCCTAAACTCCTGATCTACGCTT EQLKSGTASVVCLLNNFYPREAKCTTACAACTTGCAAAGTGGGATCCCATCAA VQWKVDNALQSGNSQESVTEQDGGTTCAGCGGCAGTGGATCTGGGACAGATT SKDSTYSLSSTLTLSKADYEKHKVTCACTCTCACCATCAACAGTCTGCAACCTGA YACEVTHQGLSSPVTKSFNRGECAGATTTTGCAACTTACTTCTGTCAACAGGCT (SEQ ID NO: 518)ATCATCCAGCCATACACTTTCGGCCCTGGG ACCAAAGTGGATATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTG ATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAG AGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGA GTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTG AGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCT GAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT (SEQ ID NO: 551)

TABLE 4B Exemplary Anti-PAC1 Antibody Heavy Chain Sequences Antibody HCHeavy Chain Amino Acid ID. Group SequenceHeavy Chain Nucleic Acid Sequence 29G4 variants 29G4v10 HC-01QVQLVESGGGVVQPGRS CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGG LRLSCAASGFTFSRFAMHTCCAGCCTGGGAGGTCCCTGCGACTCTCCTGTGCAG WVRQAPGKGLEWVAVISCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACT YDGGNKYYAESVKGRFTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGG ISRDNSKNTLYLQMNSLRGTGGCAGTTATATCATATGATGGAGGAAATAAATA AEDTALFYCARGYDVLTCTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTC GYPDYWGQGTLVTVSSACAGAGACAATTCCAAGAACACCCTGTATCTGCAAA STKGPSVFPLAPSSKSTSGTGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTT GTAALGCLVKDYFPEPVTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACC VSWNSGALTSGVHTFPACCGACTACTGGGGCCAGGGAACCCTGGTCACCGTC VLQSSGLYSLSSVVTVPSSTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCC SLGTQTYICNVNHKPSNTCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCAC KVDKKVEPKSCDKTHTCAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCC PPCPAPELLGGPSVFLFPPCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCC KPKDTLMISRTPEVTCVVTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC VDVSHEDPEVKFNWYVDAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGA GVEVHNAKTKPCEEQYGCCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACA STYRCVSVLTVLHQDWLTCTGCAACGTGAATCACAAGCCCAGCAACACCAAG NGKEYKCKVSNKALPAPIGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAA EKTISKAKGQPREPQVYTAACTCACACATGCCCACCGTGCCCAGCACCTGAACT LPPSREEMTKNQVSLTCLCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAA VKGFYPSDIAVEWESNGQACCCAAGGACACCCTCATGATCTCCCGGACCCCTGA PENNYKTTPPVLDSDGSFGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG FLYSKLTVDKSRWQQGNACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGC VFSCSVMHEALHNHYTQGTGGAGGTGCATAATGCCAAGACAAAGCCGTGCGA KSLSLSPGK (SEQ ID NO:GGAGCAGTACGGCAGCACGTACCGTTGCGTCAGCG 519)TCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCA AGGAGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTC AGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCC GGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCA CCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT AAA (SEQ ID NO: 552) 29G4v22 HC-02QVQLVESGAEVVKPGAS CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGT VKVSCKASGFTFSRFAMHAAAGCCAGGAGCTTCAGTGAAAGTCTCTTGTAAAG WVRQAPGQGLEWMGVISCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATT YDGGNKYYAESVKGRVTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGG MTRDTSTSTLYMELSSLRATGGGAGTTATTAGCTATGACGGGGGCAATAAGTA SEDTAVYYCARGYDVLTCTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGA GYPDYWGQGTLVTVSSACACGGGACACCTCAACCAGTACACTCTATATGGAA STKGPSVFPLAPSSKSTSGCTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTAT GTAALGCLVKDYFPEPVTTATTGCGCTAGGGGGTACGATGTATTGACGGGTTAT VSWNSGALTSGVHTFPACCTGATTACTGGGGGCAGGGGACACTCGTAACCGT VLQSSGLYSLSSVVTVPSSCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCC SLGTQTYICNVNHKPSNTCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCAC KVDKKVEPKSCDKTHTCAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCC PPCPAPELLGGPSVFLFPPCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCC KPKDTLMISRTPEVTCVVTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC VDVSHEDPEVKFNWYVDAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGA GVEVHNAKTKPREEQYGCCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACA STYRVVSVLTVLHQDWLTCTGCAACGTGAATCACAAGCCCAGCAACACCAAG NGKEYKCKVSNKALPAPIGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAA EKTISKAKGQPREPQVYTAACTCACACATGCCCACCGTGCCCAGCACCTGAACT LPPSREEMTKNQVSLTCLCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAA VKGFYPSDIAVEWESNGQACCCAAGGACACCCTCATGATCTCCCGGACCCCTGA PENNYKTTPPVLDSDGSFGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG FLYSKLTVDKSRWQQGNACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGC VFSCSVMHEALHNHYTQGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGA KSLSLSPGK (SEQ ID NO:GGAGCAGTACGGCAGCACGTACCGTGTGGTCAGCG 520)TCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCA AGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTC AGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCC GGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCA CCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT AAA (SEQ ID NO: 553) iPS: 420653HC-03 QVQLVESGGGVVQPGRS CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTLRLSCAASGFTFSRFAMH CCAGCCTGGGAGGTCCCTGCGACTCTCCTGTGCAGCWVRQAPGKGLEWVAVIS CTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGYIGGNKYYAESVKGRFTI GGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG SRDNSKNTLYLQMNSLRTGGCAGTTATATCATATATCGGAGGAAATAAATACT AEDTALFYCARGYDVLTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCC GYPDYWGQGTLVTVSSAAGAGACAATTCCAAGAACACCCTGTATCTGCAAAT STKGPSVFPLAPSSKSTSGGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTT GTAALGCLVKDYFPEPVTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACC VSWNSGALTSGVHTFPACCGACTACTGGGGCCAGGGAACCCTGGTCACCGTC VLQSSGLYSLSSVVTVPSSTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCC SLGTQTYICNVNHKPSNTCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCAC KVDKKVEPKSCDKTHTCAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCC PPCPAPELLGGPSVFLFPPCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCC KPKDTLMISRTPEVTCVVTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC VDVSHEDPEVKFNWYVDAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGA GVEVHNAKTKPCEEQYGCCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACA STYRCVSVLTVLHQDWLTCTGCAACGTGAATCACAAGCCCAGCAACACCAAG NGKEYKCKVSNKALPAPIGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAA EKTISKAKGQPREPQVYTAACTCACACATGCCCACCGTGCCCAGCACCTGAACT LPPSREEMTKNQVSLTCLCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAA VKGFYPSDIAVEWESNGQACCCAAGGACACCCTCATGATCTCCCGGACCCCTGA PENNYKTTPPVLDSDGSFGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG FLYSKLTVDKSRWQQGNACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGC VFSCSVMHEALHNHYTQGTGGAGGTGCATAATGCCAAGACAAAGCCGTGCGA KSLSLSPGK (SEQ ID NO:GGAGCAGTACGGCAGCACGTACCGTTGCGTCAGCG 521)TCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCA AGGAGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTC AGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCC GGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCA CCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT AAA (SEQ ID NO: 554) IPS: 420845HC-04 QVQLVESGGGVVQPGRS CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTLRLSCAASGFTFSRFAMH CCAGCCTGGGAGGTCCCTGCGACTCTCCTGTGCAGCWVRQAPGKGLEWVAVIS CTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGYQGRNKYYAESVKGRFTI GGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG SRDNSKNTLYLQMNSLRTGGCAGTTATATCATATCAGGGACGCAATAAATACT AEDTALFYCARGYDVLTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCC GYPDYWGQGTLVTVSSAAGAGACAATTCCAAGAACACCCTGTATCTGCAAAT STKGPSVFPLAPSSKSTSGGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTT GTAALGCLVKDYFPEPVTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACC VSWNSGALTSGVHTFPACCGACTACTGGGGCCAGGGAACCCTGGTCACCGTC VLQSSGLYSLSSVVTVPSSTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCC SLGTQTYICNVNHKPSNTCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCAC KVDKKVEPKSCDKTHTCAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCC PPCPAPELLGGPSVFLFPPCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCC KPKDTLMISRTPEVTCVVTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC VDVSHEDPEVKFNWYVDAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGA GVEVHNAKTKPCEEQYGCCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACA STYRCVSVLTVLHQDWLTCTGCAACGTGAATCACAAGCCCAGCAACACCAAG NGKEYKCKVSNKALPAPIGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAA EKTISKAKGQPREPQVYTAACTCACACATGCCCACCGTGCCCAGCACCTGAACT LPPSREEMTKNQVSLTCLCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAA VKGFYPSDIAVEWESNGQACCCAAGGACACCCTCATGATCTCCCGGACCCCTGA PENNYKTTPPVLDSDGSFGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG FLYSKLTVDKSRWQQGNACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGC VFSCSVMHEALHNHYTQGTGGAGGTGCATAATGCCAAGACAAAGCCGTGCGA KSLSLSPGK (SEQ ID NO:GGAGCAGTACGGCAGCACGTACCGTTGCGTCAGCG 522)TCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCA AGGAGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTC AGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCC GGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCA CCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT AAA (SEQ ID NO: 555) IPS: 420943HC-05 QVQLVESGGGVVQPGRS CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTLRLSCAASGFTFSRFAMH CCAGCCTGGGAGGTCCCTGCGACTCTCCTGTGCAGCWVRQAPGKGLEWVAVIS CTCTGGATTCACCTTCAGTAGATTTGCCATGCACTG YQGNNKYYARSVKGRFTGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG ISRDNSKNTLYLQMNSLRTGGCAGTTATATCATATCAGGGAAACAATAAATAC AEDTALFYCARGYDVLTTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCC GYPDYWGQGTLVTVSSAAGAGACAATTCCAAGAACACCCTGTATCTGCAAAT STKGPSVFPLAPSSKSTSGGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTT GTAALGCLVKDYFPEPVTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACC VSWNSGALTSGVHTFPACCGACTACTGGGGCCAGGGAACCCTGGTCACCGTC VLQSSGLYSLSSVVTVPSSTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCC SLGTQTYICNVNHKPSNTCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCAC KVDKKVEPKSCDKTHTCAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCC PPCPAPELLGGPSVFLFPPCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCC KPKDTLMISRTPEVTCVVTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC VDVSHEDPEVKFNWYVDAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGA GVEVHNAKTKPCEEQYGCCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACA STYRCVSVLTVLHQDWLTCTGCAACGTGAATCACAAGCCCAGCAACACCAAG NGKEYKCKVSNKALPAPIGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAA EKTISKAKGQPREPQVYTAACTCACACATGCCCACCGTGCCCAGCACCTGAACT LPPSREEMTKNQVSLTCLCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAA VKGFYPSDIAVEWESNGQACCCAAGGACACCCTCATGATCTCCCGGACCCCTGA PENNYKTTPPVLDSDGSFGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG FLYSKLTVDKSRWQQGNACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGC VFSCSVMHEALHNHYTQGTGGAGGTGCATAATGCCAAGACAAAGCCGTGCGA KSLSLSPGK (SEQ ID NO:GGAGCAGTACGGCAGCACGTACCGTTGCGTCAGCG 523)TCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCA AGGAGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTC AGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCC GGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCA CCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT AAA (SEQ ID NO: 556) iPS: 421873HC-06 QVQLVESGGGVVQPGRS CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTLRLSCAASGFTFSKFAMH CCAGCCTGGGAGGTCCCTGCGACTCTCCTGTGCAGCWVRQAPGKGLEWVAVIS CTCTGGATTCACCTTCAGTAAGTTTGCCATGCACTGYRGGNKYYAESVKGRFTI GGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG SRDNSKNTLYLQMNSLRTGGCAGTTATATCATATCGCGGAGGAAATAAATAC AEDTALFYCARGYDLLTTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCC GYPDYWGQGTLVTVSSAAGAGACAATTCCAAGAACACCCTGTATCTGCAAAT STKGPSVFPLAPSSKSTSGGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTT GTAALGCLVKDYFPEPVTACTGTGCGAGAGGATACGATCTGTTGACTGGTTACC VSWNSGALTSGVHTFPACCGACTACTGGGGCCAGGGAACCCTGGTCACCGTC VLQSSGLYSLSSVVTVPSSTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCC SLGTQTYICNVNHKPSNTCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCAC KVDKKVEPKSCDKTHTCAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCC PPCPAPELLGGPSVFLFPPCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCC KPKDTLMISRTPEVTCVVTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC VDVSHEDPEVKFNWYVDAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGA GVEVHNAKTKPCEEQYGCCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACA STYRCVSVLTVLHQDWLTCTGCAACGTGAATCACAAGCCCAGCAACACCAAG NGKEYKCKVSNKALPAPIGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAA EKTISKAKGQPREPQVYTAACTCACACATGCCCACCGTGCCCAGCACCTGAACT LPPSREEMTKNQVSLTCLCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAA VKGFYPSDIAVEWESNGQACCCAAGGACACCCTCATGATCTCCCGGACCCCTGA PENNYKTTPPVLDSDGSFGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG FLYSKLTVDKSRWQQGNACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGC VFSCSVMHEALHNHYTQGTGGAGGTGCATAATGCCAAGACAAAGCCGTGCGA KSLSLSPGK (SEQ ID NO:GGAGCAGTACGGCAGCACGTACCGTTGCGTCAGCG 524)TCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCA AGGAGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTC AGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCC GGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCA CCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT AAA (SEQ ID NO: 557) iPS: 420889HC-07 QVQLVESGGGVVQPGRS CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTLRLSCAASGFTFSRFAMH CCAGCCTGGGAGGTCCCTGCGACTCTCCTGTGCAGCWVRQAPGKGLEWVAVIS CTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGYIGGNKYYAESVKGRFTI GGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG SRDNSKNTLYLQMNSLRTGGCAGTTATATCATATATCGGAGGAAATAAATACT AEDTALFYCARGYDILTGATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCC YPDYWGQGTLVTVSSASAGAGACAATTCCAAGAACACCCTGTATCTGCAAAT TKGPSVFPLAPSSKSTSGGGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTT TAALGCLVKDYFPEPVTVACTGTGCGAGAGGATACGATATCTTGACTGGTTACC SWNSGALTSGVHTFPAVLCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTC QSSGLYSLSSVVTVPSSSLTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCC GTQTYICNVNHKPSNTKVCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCAC DKKVEPKSCDKTHTCPPCAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCC PAPELLGGPSVFLFPPKPKCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCC DTLMISRTPEVTCVVVDVTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC SHEDPEVKFNWYVDGVEAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGA VHNAKTKPCEEQYGSTYCCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACA RCVSVLTVLHQDWLNGKTCTGCAACGTGAATCACAAGCCCAGCAACACCAAG EYKCKVSNKALPAPIEKTIGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAA SKAKGQPREPQVYTLPPSAACTCACACATGCCCACCGTGCCCAGCACCTGAACT REEMTKNQVSLTCLVKGCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAA FYPSDIAVEWESNGQPENACCCAAGGACACCCTCATGATCTCCCGGACCCCTGA NYKTTPPVLDSDGSFFLYGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG SKLTVDKSRWQQGNVFSACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGC CSVMHEALHNHYTQKSLGTGGAGGTGCATAATGCCAAGACAAAGCCGTGCGA SLSPGK (SEQ ID NO: 525)GGAGCAGTACGGCAGCACGTACCGTTGCGTCAGCG TCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGCCCTC CCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGC CCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGC GACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGG ACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTC TTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT AAA (SEQ ID NO: 558) iPS: 421091HC-08 QVQLVESGGGVVQPGRS CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTLRLSCAASGFTFSRFAMH CCAGCCTGGGAGGTCCCTGCGACTCTCCTGTGCAGCWVRQAPGKGLEWVAVIS CTCTGGATTCACCTTCAGTAGATTTGCCATGCACTG YNGRNKYYARSVKGRFTGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG ISRDNSKNTLYLQMNSLRTGGCAGTTATATCATATAACGGACGCAATAAATACT AEDTALFYCARGYDILTGATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCA YPDYWGQGTLVTVSSASGAGACAATTCCAAGAACACCCTGTATCTGCAAATG TKGPSVFPLAPSSKSTSGGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTA TAALGCLVKDYFPEPVTVCTGTGCGAGAGGATACGATATCTTGACTGGTTACCC SWNSGALTSGVHTFPAVLCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCT QSSGLYSLSSVVTVPSSSLCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCC GTQTYICNVNHKPSNTKVTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACA DKKVEPKSCDKTHTCPPCGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCC PAPELLGGPSVFLFPPKPKGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCT DTLMISRTPEVTCVVVDVGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA SHEDPEVKFNWYVDGVEGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGAC VHNAKTKPCEEQYGSTYCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACAT RCVSVLTVLHQDWLNGKCTGCAACGTGAATCACAAGCCCAGCAACACCAAGG EYKCKVSNKALPAPIEKTITGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAA SKAKGQPREPQVYTLPPSACTCACACATGCCCACCGTGCCCAGCACCTGAACTC REEMTKNQVSLTCLVKGCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAA FYPSDIAVEWESNGQPENCCCAAGGACACCCTCATGATCTCCCGGACCCCTGAG NYKTTPPVLDSDGSFFLYGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGA SKLTVDKSRWQQGNVFSCCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCG CSVMHEALHNHYTQKSLTGGAGGTGCATAATGCCAAGACAAAGCCGTGCGAG SLSPGK (SEQ ID NO: 526)GAGCAGTACGGCAGCACGTACCGTTGCGTCAGCGT CCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGCCCTC CCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGC CCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGC GACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGG ACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTC TTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT AAA (SEQ ID NO: 559) iPS: 421051HC-05 QVQLVESGGGVVQPGRS CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTLRLSCAASGFTFSRFAMH CCAGCCTGGGAGGTCCCTGCGACTCTCCTGTGCAGCWVRQAPGKGLEWVAVIS CTCTGGATTCACCTTCAGTAGATTTGCCATGCACTG YQGNNKYYARSVKGRFTGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG ISRDNSKNTLYLQMNSLRTGGCAGTTATATCATATCAGGGAAACAATAAATAC AEDTALFYCARGYDVLTTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCC GYPDYWGQGTLVTVSSAAGAGACAATTCCAAGAACACCCTGTATCTGCAAAT STKGPSVFPLAPSSKSTSGGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTT GTAALGCLVKDYFPEPVTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACC VSWNSGALTSGVHTFPACCGACTACTGGGGCCAGGGAACCCTGGTCACCGTC VLQSSGLYSLSSVVTVPSSTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCC SLGTQTYICNVNHKPSNTCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCAC KVDKKVEPKSCDKTHTCAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCC PPCPAPELLGGPSVFLFPPCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCC KPKDTLMISRTPEVTCVVTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC VDVSHEDPEVKFNWYVDAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGA GVEVHNAKTKPCEEQYGCCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACA STYRCVSVLTVLHQDWLTCTGCAACGTGAATCACAAGCCCAGCAACACCAAG NGKEYKCKVSNKALPAPIGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAA EKTISKAKGQPREPQVYTAACTCACACATGCCCACCGTGCCCAGCACCTGAACT LPPSREEMTKNQVSLTCLCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAA VKGFYPSDIAVEWESNGQACCCAAGGACACCCTCATGATCTCCCGGACCCCTGA PENNYKTTPPVLDSDGSFGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG FLYSKLTVDKSRWQQGNACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGC VFSCSVMHEALHNHYTQGTGGAGGTGCATAATGCCAAGACAAAGCCGTGCGA KSLSLSPGK (SEQ ID NO:GGAGCAGTACGGCAGCACGTACCGTTGCGTCAGCG 523)TCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCA AGGAGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTC AGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCC GGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCA CCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT AAA (SEQ ID NO: 556) iPS: 480711HC-09 QVQLVESGGGVVQPGRS CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGLRLSCAASGFTFSRFAMH TCCAGCCTGGGAGGTCCCTGCGACTCTCCTGTGCAGWVRQAPGKGLEWVGVIN CCTCTGGATTCACCTTCAGTAGATTTGCCATGCACT YRGHGKYYAESVKGRFTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGG VSRDNSKNTLYLQMNSLGTGGGTGTTATCAACTATCGTGGACATGGTAAATAC RAEDTALFYCARGYDVLTATGCAGAGTCCGTGAAGGGCCGGTTCACCGTGTCC TGYPDYWGQGTLVTVSSAGAGACAATTCCAAGAACACCCTGTATCTGCAAAT ASTKGPSVFPLAPSSKSTSGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTT GGTAALGCLVKDYFPEPACTGTGCGAGAGGATACGATGTTTTGACTGGTTACC VTVSWNSGALTSGVHTFPCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTG AVLQSSGLYSLSSVVTVPTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCC SSSLGTQTYICNVNHKPSCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCAC NTKVDKKVEPKSCDKTHAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCC TCPPCPAPELLGGPSVFLFCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCC PPKPKDTLMISRTPEVTCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC VVVDVSHEDPEVKFNWYAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGA VDGVEVHNAKTKPCEEQCCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACA YGSTYRCVSVLTVLHQDTCTGCAACGTGAATCACAAGCCCAGCAACACCAAG WLNGKEYKCKVSNKALPGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAA APIEKTISKAKGQPREPQVAACTCACACATGCCCACCGTGCCCAGCACCTGAACT YTLPPSREEMTKNQVSLTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAA CLVKGFYPSDIAVEWESNACCCAAGGACACCCTCATGATCTCCCGGACCCCTGA GQPENNYKTTPPVLDSDGGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG SFFLYSKLTVDKSRWQQACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGC GNVFSCSVMHEALHNHYGTGGAGGTGCATAATGCCAAGACAAAGCCGTGCGA TQKSLSLSPGK (SEQ IDGGAGCAGTACGGCAGCACGTACCGTTGCGTCAGCG NO: 527)TCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCA AGGAGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTC AGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCC GGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCA CCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT AAA (SEQ ID NO: 560) iPS: 480706HC-10 QVQLVESGGGVVQPGRS CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTLRLSCAASGFTFSRFAMH CCAGCCTGGGAGGTCCCTGCGACTCTCCTGTGCAGCWVRQAPGKGLEWVGVIS CTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGFSGGSKYYAESVKGRFTL GGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG SRDNSKNTLYLQMNSLRTGGGTGTTATATCTTTTTCTGGAGGTTCTAAATACT AEDTALFYCARGYDVLTATGCAGAGTCCGTGAAGGGCCGGTTCACCTTGTCCA GYPDYWGQGTLVTVSSAGAGACAATTCCAAGAACACCCTGTATCTGCAAATG STKGPSVFPLAPSSKSTSGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTA GTAALGCLVKDYFPEPVTCTGTGCGAGAGGATACGATGTTTTGACTGGTTACCC VSWNSGALTSGVHTFPACGACTACTGGGGCCAGGGAACCCTGGTCACCGTGT VLQSSGLYSLSSVVTVPSSCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCC SLGTQTYICNVNHKPSNTTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACA KVDKKVEPKSCDKTHTCGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCC PPCPAPELLGGPSVFLFPPGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCT KPKDTLMISRTPEVTCVVGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA VDVSHEDPEVKFNWYVDGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGAC GVEVHNAKTKPCEEQYGCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACAT STYRCVSVLTVLHQDWLCTGCAACGTGAATCACAAGCCCAGCAACACCAAGG NGKEYKCKVSNKALPAPITGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAA EKTISKAKGQPREPQVYTACTCACACATGCCCACCGTGCCCAGCACCTGAACTC LPPSREEMTKNQVSLTCLCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAA VKGFYPSDIAVEWESNGQCCCAAGGACACCCTCATGATCTCCCGGACCCCTGAG PENNYKTTPPVLDSDGSFGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGA FLYSKLTVDKSRWQQGNCCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCG VFSCSVMHEALHNHYTQTGGAGGTGCATAATGCCAAGACAAAGCCGTGCGAG KSLSLSPGK (SEQ ID NO:GAGCAGTACGGCAGCACGTACCGTTGCGTCAGCGT 528)CCTCACCGTCCTGCACCAGGACTGGCTGAATGGCA AGGAGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTC AGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCC GGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCA CCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT AAA (SEQ ID NO: 561) IPS: 480713HC-11 QVQLVESGGGVVQPGRS CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTLRLSCAASGFTFSRFAMH CCAGCCTGGGAGGTCCCTGCGACTCTCCTGTGCAGCWVRQAPGKGLEWVGVIS CTCTGGATTCACCTTCAGTAGATTTGCCATGCACTG YTGQFKYYAESVKGRFTGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG VSRDNSKNTLYLQMNSLTGGGTGTTATCTCTTATACTGGACAGTTCAAATACT RAEDTALFYCARGYDVLATGCAGAGTCCGTGAAGGGCCGGTTCACCGTGTCC TGYPDYWGQGTLVTVSSAGAGACAATTCCAAGAACACCCTGTATCTGCAAAT ASTKGPSVFPLAPSSKSTSGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTT GGTAALGCLVKDYFPEPACTGTGCGAGAGGATACGATGTTTTGACTGGTTACC VTVSWNSGALTSGVHTFPCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTG AVLQSSGLYSLSSVVTVPTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCC SSSLGTQTYICNVNHKPSCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCAC NTKVDKKVEPKSCDKTHAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCC TCPPCPAPELLGGPSVFLFCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCC PPKPKDTLMISRTPEVTCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTAC VVVDVSHEDPEVKFNWYAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGA VDGVEVHNAKTKPCEEQCCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACA YGSTYRCVSVLTVLHQDTCTGCAACGTGAATCACAAGCCCAGCAACACCAAG WLNGKEYKCKVSNKALPGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAA APIEKTISKAKGQPREPQVAACTCACACATGCCCACCGTGCCCAGCACCTGAACT YTLPPSREEMTKNQVSLTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAA CLVKGFYPSDIAVEWESNACCCAAGGACACCCTCATGATCTCCCGGACCCCTGA GQPENNYKTTPPVLDSDGGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG SFFLYSKLTVDKSRWQQACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGC GNVFSCSVMHEALHNHYGTGGAGGTGCATAATGCCAAGACAAAGCCGTGCGA TQKSLSLSPGK (SEQ IDGGAGCAGTACGGCAGCACGTACCGTTGCGTCAGCG NO: 529)TCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCA AGGAGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTC AGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCC GGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCA CCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT AAA (SEQ ID NO: 562) 19H8 variants19H8 HC-12 QVQLQQSGPGLVKPSQTL CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTSLTCAISGDSVSSNSATW GAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCATNWIRQSPSRGLEWLGRTY CTCCGGGGACAGTGTCTCTAGCAACAGTGCTACTTGYRSKWSNHYAVSVKSRIT GAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGINPDTSKSQFSLQLNSVTP AGTGGCTGGGAAGGACATATTACAGGTCCAAGTGG EDTAVYYCARGTWKQLTCTAATCATTATGCAGTATCTGTGAAAAGTCGAATC WFLDHWGQGTLVTVSSAACCATCAACCCCGACACGTCCAAGAGCCAGTTCTCC STKGPSVFPLAPSSKSTSGCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCT GTAALGCLVKDYFPEPVTGTGTATTACTGTGCAAGAGGAACGTGGAAACAGCT VSWNSGALTSGVHTFPAATGGTTCCTTGACCACTGGGGCCAGGGAACCCTGGT VLQSSGLYSLSSVVTVPSSCACCGTGTCTAGTGCCTCCACCAAGGGCCCATCGGT SLGTQTYICNVNHKPSNTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGG KVDKKVEPKSCDKTHTCGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACT PPCPAPELLGGPSVFLFPPACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCA KPKDTLMISRTPEVTCVVGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCT VDVSHEDPEVKFNWYVDGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGC GVEVHNAKTKPCEEQYGGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA STYRCVSVLTVLHQDWLGACCTACATCTGCAACGTGAATCACAAGCCCAGCA NGKEYKCKVSNKALPAPIACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCT EKTISKAKGQPREPQVYTTGTGACAAAACTCACACATGCCCACCGTGCCCAGC LPPSREEMTKNQVSLTCLACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTT VKGFYPSDIAVEWESNGQCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCG PENNYKTTPPVLDSDGSFGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGA FLYSKLTVDKSRWQQGNGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTAC VFSCSVMHEALHNHYTQGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA KSLSLSPGK (SEQ ID NO:GCCGTGCGAGGAGCAGTACGGCAGCACGTACCGTT 530)GCGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGC TGAATGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTC CAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAG AACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAA TGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATA GCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCT CTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGCAAA (SEQ ID NO: 563) iPS: 448730 HC-13 QVQLQQSGPGLVKPSQTLCAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGT SLTCAISGDSVSNRLATWGAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCAT NWIRQSPSRGLEWLGRTYCTCCGGGGACAGTGTCTCTAACCGTCTGGCTACTTG YRGKWKNHYAVSVKSRIGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTG TINPDTSKSQFSLQLNSVTAGTGGCTGGGAAGGACATACTACAGGGGTAAATGG PEDTAVYYCARGVWIGNAAAAATCATTATGCAGTATCTGTGAAAAGTCGAAT WFLDHWGQGTLVTVSSAAACCATCAACCCCGACACGTCCAAGAGCCAGTTCT STKGPSVFPLAPSSKSTSGCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACG GTAALGCLVKDYFPEPVTGCTGTGTATTACTGTGCAAGAGGAGTTTGGATCGGT VSWNSGALTSGVHTFPAAACTGGTTCCTGGACCACTGGGGCCAGGGAACCCT VLQSSGLYSLSSVVTVPSSGGTCACCGTGTCCTCAGCCTCCACCAAGGGCCCATC SLGTQTYICNVNHKPSNTGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTC KVDKKVEPKSCDKTHTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG PPCPAPELLGGPSVFLFPPACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACT KPKDTLMISRTPEVTCVVCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCG VDVSHEDPEVKFNWYVDGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGC GVEVHNAKTKPCEEQYGAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCAC STYRCVSVLTVLHQDWLCCAGACCTACATCTGCAACGTGAATCACAAGCCCA NGKEYKCKVSNKALPAPIGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAA EKTISKAKGQPREPQVYTTCTTGTGACAAAACTCACACATGCCCACCGTGCCCA LPPSREEMTKNQVSLTCLGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTC VKGFYPSDIAVEWESNGQTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCC PENNYKTTPPVLDSDGSFCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGT FLYSKLTVDKSRWQQGNGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGT VFSCSVMHEALHNHYTQACGTGGACGGCGTGGAGGTGCATAATGCCAAGACA KSLSLSPGK (SEQ ID NO:AAGCCGTGCGAGGAGCAGTACGGCAGCACGTACCG 531)TTGCGTCAGCGTCCTCACCGTCCTGCACCAGGACTG GCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATC TCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCA AGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAG CAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCT ATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAG GCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA (SEQ ID NO: 564) iPS: 448195 HC-14 QVQLQQSGPGLVKPSQTLCAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGT SLTCAISGDSVSNKQATWGAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCAT NWIRQSPSRGLEWLGRTYCTCCGGGGACAGTGTCTCTAACAAACAGGCTACTTG YRGKWKNHYAVSVKSRIGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTG TINPDTSKSQFSLQLNSVTAGTGGCTGGGAAGGACATACTACAGGGGTAAATGG PEDTAVYYCARGMWNQAAAAATCATTATGCAGTATCTGTGAAAAGTCGAAT NWFLDHWGQGTLVTVSSAACCATCAACCCCGACACGTCCAAGAGCCAGTTCT ASTKGPSVFPLAPSSKSTSCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACG GGTAALGCLVKDYFPEPGCTGTGTATTACTGTGCAAGAGGAATGTGGAACCA VTVSWNSGALTSGVHTFPGAACTGGTTCCTGGACCACTGGGGCCAGGGAACCC AVLQSSGLYSLSSVVTVPTGGTCACCGTGTCCTCAGCCTCCACCAAGGGCCCAT SSSLGTQTYICNVNHKPSCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCT NTKVDKKVEPKSCDKTHCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAG TCPPCPAPELLGGPSVFLFGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAA PPKPKDTLMISRTPEVTCCTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCC VVVDVSHEDPEVKFNWYGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAG VDGVEVHNAKTKPCEEQCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCA YGSTYRCVSVLTVLHQDCCCAGACCTACATCTGCAACGTGAATCACAAGCCC WLNGKEYKCKVSNKALPAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAA APIEKTISKAKGQPREPQVATCTTGTGACAAAACTCACACATGCCCACCGTGCCC YTLPPSREEMTKNQVSLTAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCT CLVKGFYPSDIAVEWESNCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTC GQPENNYKTTPPVLDSDGCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACG SFFLYSKLTVDKSRWQQTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGG GNVFSCSVMHEALHNHYTACGTGGACGGCGTGGAGGTGCATAATGCCAAGAC TQKSLSLSPGK (SEQ IDAAAGCCGTGCGAGGAGCAGTACGGCAGCACGTACC NO: 532)GTTGCGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACC AAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG CAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTC CCTGTCTCCGGGTAAA (SEQ ID NO: 565)iPS: 448788 HC-15 QVQLQQSGPGLVKPSQTL CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTSLTCAISGDSVSSRQATW GAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCATNWIRQSPSRGLEWLGRTY CTCCGGGGACAGTGTCTCTTCTCGTCAGGCTACTTGYRGKWKNHYAVSVKSRI GAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGTINPDTSKSQFSLQLNSVT AGTGGCTGGGAAGGACATACTACAGGGGTAAATGG PEDTAVYYCARGMWQGAAAAATCATTATGCAGTATCTGTGAAAAGTCGAAT NWFLDHWGQGTLVTVSSAACCATCAACCCCGACACGTCCAAGAGCCAGTTCT ASTKGPSVFPLAPSSKSTSCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACG GGTAALGCLVKDYFPEPGCTGTGTATTACTGTGCAAGAGGAATGTGGCAGGG VTVSWNSGALTSGVHTFPTAACTGGTTCCTGGACCACTGGGGCCAGGGAACCC AVLQSSGLYSLSSVVTVPTGGTCACCGTGTCCTCAGCCTCCACCAAGGGCCCAT SSSLGTQTYICNVNHKPSCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCT NTKVDKKVEPKSCDKTHCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAG TCPPCPAPELLGGPSVFLFGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAA PPKPKDTLMISRTPEVTCCTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCC VVVDVSHEDPEVKFNWYGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAG VDGVEVHNAKTKPCEEQCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCA YGSTYRCVSVLTVLHQDCCCAGACCTACATCTGCAACGTGAATCACAAGCCC WLNGKEYKCKVSNKALPAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAA APIEKTISKAKGQPREPQVATCTTGTGACAAAACTCACACATGCCCACCGTGCCC YTLPPSREEMTKNQVSLTAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCT CLVKGFYPSDIAVEWESNCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTC GQPENNYKTTPPVLDSDGCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACG SFFLYSKLTVDKSRWQQTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGG GNVFSCSVMHEALHNHYTACGTGGACGGCGTGGAGGTGCATAATGCCAAGAC TQKSLSLSPGK (SEQ IDAAAGCCGTGCGAGGAGCAGTACGGCAGCACGTACC NO: 533)GTTGCGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACC AAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG CAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTC CCTGTCTCCGGGTAAA (SEQ ID NO: 566)iPS: 448901 HC-16 QVQLQQSGPGLVKPSQTL CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTSLTCAISGDSVSNRLATW GAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCATNWIRQSPSRGLEWLGRTY CTCCGGGGACAGTGTCTCTAACCGTCTGGCTACTTGYRGKWKNHYAVSVKSRI GAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGTINPDTSKSQFSLQLNSVT AGTGGCTGGGAAGGACATACTACAGGGGTAAATGGPEDTAVYYCARGRWEGD AAAAATCATTATGCAGTATCTGTGAAAAGTCGAAT WFFDHWGQGTLVTVSSAAACCATCAACCCCGACACGTCCAAGAGCCAGTTCT STKGPSVFPLAPSSKSTSGCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACG GTAALGCLVKDYFPEPVTGCTGTGTATTACTGTGCAAGAGGACGTTGGGAAGG VSWNSGALTSGVHTFPATGACTGGTTCTTCGACCACTGGGGCCAGGGAACCCT VLQSSGLYSLSSVVTVPSSGGTCACCGTGTCCTCAGCCTCCACCAAGGGCCCATC SLGTQTYICNVNHKPSNTGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTC KVDKKVEPKSCDKTHTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG PPCPAPELLGGPSVFLFPPACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACT KPKDTLMISRTPEVTCVVCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCG VDVSHEDPEVKFNWYVDGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGC GVEVHNAKTKPCEEQYGAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCAC STYRCVSVLTVLHQDWLCCAGACCTACATCTGCAACGTGAATCACAAGCCCA NGKEYKCKVSNKALPAPIGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAA EKTISKAKGQPREPQVYTTCTTGTGACAAAACTCACACATGCCCACCGTGCCCA LPPSREEMTKNQVSLTCLGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTC VKGFYPSDIAVEWESNGQTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCC PENNYKTTPPVLDSDGSFCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGT FLYSKLTVDKSRWQQGNGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGT VFSCSVMHEALHNHYTQACGTGGACGGCGTGGAGGTGCATAATGCCAAGACA KSLSLSPGK (SEQ ID NO:AAGCCGTGCGAGGAGCAGTACGGCAGCACGTACCG 534)TTGCGTCAGCGTCCTCACCGTCCTGCACCAGGACTG GCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATC TCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCA AGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAG CAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCT ATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAG GCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA (SEQ ID NO: 567) iPS: 448689 HC-17 QVQLQQSGPGLVKPSQTLCAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGT SLTCAISGDSVSNRLATWGAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCAT NWIRQSPSRGLEWLGRTYCTCCGGGGACAGTGTCTCTAACCGTCTGGCTACTTG YRGKWKNHYAVSVKSRIGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTG TINPDTSKSQFSLQLNSVTAGTGGCTGGGAAGGACATACTACAGGGGTAAATGG PEDTAVYYCARGTWNQDAAAAATCATTATGCAGTATCTGTGAAAAGTCGAAT WFLDHWGQGTLVTVSSAAACCATCAACCCCGACACGTCCAAGAGCCAGTTCT STKGPSVFPLAPSSKSTSGCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACG GTAALGCLVKDYFPEPVTGCTGTGTATTACTGTGCAAGAGGAACTTGGAACCA VSWNSGALTSGVHTFPAGGACTGGTTCCTGGACCACTGGGGCCAGGGAACCC VLQSSGLYSLSSVVTVPSSTGGTCACCGTGTCCTCAGCCTCCACCAAGGGCCCAT SLGTQTYICNVNHKPSNTCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCT KVDKKVEPKSCDKTHTCCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAG PPCPAPELLGGPSVFLFPPGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAA KPKDTLMISRTPEVTCVVCTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCC VDVSHEDPEVKFNWYVDGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAG GVEVHNAKTKPCEEQYGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCA STYRCVSVLTVLHQDWLCCCAGACCTACATCTGCAACGTGAATCACAAGCCC NGKEYKCKVSNKALPAPIAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAA EKTISKAKGQPREPQVYTATCTTGTGACAAAACTCACACATGCCCACCGTGCCC LPPSREEMTKNQVSLTCLAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCT VKGFYPSDIAVEWESNGQCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTC PENNYKTTPPVLDSDGSFCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACG FLYSKLTVDKSRWQQGNTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGG VFSCSVMHEALHNHYTQTACGTGGACGGCGTGGAGGTGCATAATGCCAAGAC KSLSLSPGK (SEQ ID NO:AAAGCCGTGCGAGGAGCAGTACGGCAGCACGTACC 535)GTTGCGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACC AAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG CAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTC CCTGTCTCCGGGTAAA (SEQ ID NO: 568)iPS: 448202 HC-17 QVQLQQSGPGLVKPSQTL CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTSLTCAISGDSVSNRLATW GAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCATNWIRQSPSRGLEWLGRTY CTCCGGGGACAGTGTCTCTAACCGTCTGGCTACTTGYRGKWKNHYAVSVKSRI GAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGTINPDTSKSQFSLQLNSVT AGTGGCTGGGAAGGACATACTACAGGGGTAAATGGPEDTAVYYCARGTWNQD AAAAATCATTATGCAGTATCTGTGAAAAGTCGAAT WFLDHWGQGTLVTVSSAAACCATCAACCCCGACACGTCCAAGAGCCAGTTCT STKGPSVFPLAPSSKSTSGCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACG GTAALGCLVKDYFPEPVTGCTGTGTATTACTGTGCAAGAGGAACTTGGAACCA VSWNSGALTSGVHTFPAGGACTGGTTCCTGGACCACTGGGGCCAGGGAACCC VLQSSGLYSLSSVVTVPSSTGGTCACCGTGTCCTCAGCCTCCACCAAGGGCCCAT SLGTQTYICNVNHKPSNTCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCT KVDKKVEPKSCDKTHTCCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAG PPCPAPELLGGPSVFLFPPGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAA KPKDTLMISRTPEVTCVVCTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCC VDVSHEDPEVKFNWYVDGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAG GVEVHNAKTKPCEEQYGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCA STYRCVSVLTVLHQDWLCCCAGACCTACATCTGCAACGTGAATCACAAGCCC NGKEYKCKVSNKALPAPIAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAA EKTISKAKGQPREPQVYTATCTTGTGACAAAACTCACACATGCCCACCGTGCCC LPPSREEMTKNQVSLTCLAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCT VKGFYPSDIAVEWESNGQCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTC PENNYKTTPPVLDSDGSFCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACG FLYSKLTVDKSRWQQGNTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGG VFSCSVMHEALHNHYTQTACGTGGACGGCGTGGAGGTGCATAATGCCAAGAC KSLSLSPGK (SEQ ID NO:AAAGCCGTGCGAGGAGCAGTACGGCAGCACGTACC 535)GTTGCGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACC AAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG CAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTC CCTGTCTCCGGGTAAA (SEQ ID NO: 568)iPS: 452128 HC-14 QVQLQQSGPGLVKPSQTL CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTSLTCAISGDSVSNKQATW GAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCATNWIRQSPSRGLEWLGRTY CTCCGGGGACAGTGTCTCTAACAAACAGGCTACTTGYRGKWKNHYAVSVKSRI GAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGTINPDTSKSQFSLQLNSVT AGTGGCTGGGAAGGACATACTACAGGGGTAAATGG PEDTAVYYCARGMWNQAAAAATCATTATGCAGTATCTGTGAAAAGTCGAAT NWFLDHWGQGTLVTVSSAACCATCAACCCCGACACGTCCAAGAGCCAGTTCT ASTKGPSVFPLAPSSKSTSCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACG GGTAALGCLVKDYFPEPGCTGTGTATTACTGTGCAAGAGGAATGTGGAACCA VTVSWNSGALTSGVHTFPGAACTGGTTCCTGGACCACTGGGGCCAGGGAACCC AVLQSSGLYSLSSVVTVPTGGTCACCGTGTCCTCAGCCTCCACCAAGGGCCCAT SSSLGTQTYICNVNHKPSCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCT NTKVDKKVEPKSCDKTHCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAG TCPPCPAPELLGGPSVFLFGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAA PPKPKDTLMISRTPEVTCCTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCC VVVDVSHEDPEVKFNWYGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAG VDGVEVHNAKTKPCEEQCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCA YGSTYRCVSVLTVLHQDCCCAGACCTACATCTGCAACGTGAATCACAAGCCC WLNGKEYKCKVSNKALPAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAA APIEKTISKAKGQPREPQVATCTTGTGACAAAACTCACACATGCCCACCGTGCCC YTLPPSREEMTKNQVSLTAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCT CLVKGFYPSDIAVEWESNCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTC GQPENNYKTTPPVLDSDGCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACG SFFLYSKLTVDKSRWQQTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGG GNVFSCSVMHEALHNHYTACGTGGACGGCGTGGAGGTGCATAATGCCAAGAC TQKSLSLSPGK (SEQ IDAAAGCCGTGCGAGGAGCAGTACGGCAGCACGTACC NO: 532)GTTGCGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACC AAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG CAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTC CCTGTCTCCGGGTAAA (SEQ ID NO: 565)iPS: 448924 HC-18 QVQLQQSGPGLVKPSQTL CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTSLTCAISGDSVSSRYATW GAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCATNWIRQSPSRGLEWLGRTY CTCCGGGGACAGTGTCTCTTCTCGTTACGCTACTTGYRGQWKNHYAVSVKSRI GAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGTINPDTSKSQFSLQLNSVT AGTGGCTGGGAAGGACATACTACAGGGGTCAGTGG PEDTAVYYCAAAAAATCATTATGCAGTATCTGTGAAAAGTCGAAT RGMWNQNWFLDHWGQAACCATCAACCCCGACACGTCCAAGAGCCAGTTCT GTLVTVSSASTKGPSVFPCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACG LAPSSKSTSGGTAALGCLGCTGTGTATTACTGTGCAAGAGGAATGTGGAACCA VKDYFPEPVTVSWNSGAGAACTGGTTCCTGGACCACTGGGGCCAGGGAACCC LTSGVHTFPAVLQSSGLYTGGTCACCGTGTCCTCAGCCTCCACCAAGGGCCCAT SLSSVVTVPSSSLGTQTYICGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCT CNVNHKPSNTKVDKKVECTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAG PKSCDKTHTCPPCPAPELGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAA LGGPSVFLFPPKPKDTLMICTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCC SRTPEVTCVVVDVSHEDPGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAG EVKFNWYVDGVEVHNACAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCA KTKPCEEQYGSTYRCVSVCCCAGACCTACATCTGCAACGTGAATCACAAGCCC LTVLHQDWLNGKEYKCKAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAA VSNKALPAPIEKTISKAKGATCTTGTGACAAAACTCACACATGCCCACCGTGCCC QPREPQVYTLPPSREEMTAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCT KNQVSLTCLVKGFYPSDICTTCCCCCCAAAACCCAAGGACACCCTCATGATCTC AVEWESNGQPENNYKTTCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACG PPVLDSDGSFFLYSKLTVTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGG DKSRWQQGNVFSCSVMHTACGTGGACGGCGTGGAGGTGCATAATGCCAAGAC EALHNHYTQKSLSLSPGKAAAGCCGTGCGAGGAGCAGTACGGCAGCACGTACC (SEQ ID NO: 536)GTTGCGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACC AAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG CAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTC CCTGTCTCCGGGTAAA (SEQ ID NO: 569)3574 HC-14 QVQLQQSGPGLVKPSQTL CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTSLTCAISGDSVSNKQATW GAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCATNWIRQSPSRGLEWLGRTY CTCCGGGGACAGTGTCTCTAACAAACAGGCTACTTGYRGKWKNHYAVSVKSRI GAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGTINPDTSKSQFSLQLNSVT AGTGGCTGGGAAGGACATACTACAGGGGTAAATGG PEDTAVYYCARGMWNQAAAAATCATTATGCAGTATCTGTGAAAAGTCGAAT NWFLDHWGQGTLVTVSSAACCATCAACCCCGACACGTCCAAGAGCCAGTTCT ASTKGPSVFPLAPSSKSTSCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACG GGTAALGCLVKDYFPEPGCTGTGTATTACTGTGCAAGAGGAATGTGGAACCA VTVSWNSGALTSGVHTFPGAACTGGTTCCTGGACCACTGGGGCCAGGGAACCC AVLQSSGLYSLSSVVTVPTGGTCACCGTGTCCTCAGCCTCCACCAAGGGC SSSLGTQTYICNVNHKPSCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGC NTKVDKKVEPKSCDKTHACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGT TCPPCPAPELLGGPSVFLFCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT PPKPKDTLMISRTPEVTCGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACC VVVDVSHEDPEVKFNWYTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC VDGVEVHNAKTKPCEEQCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTG YGSTYRCVSVLTVLHQDGGCACCCAGACCTACATCTGCAACGTGAATCACAA WLNGKEYKCKVSNKALPGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGC APIEKTISKAKGQPREPQVCCAAATCTTGTGACAAAACTCACACATGCCCACCGT YTLPPSREEMTKNQVSLTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTC CLVKGFYPSDIAVEWESNTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATG GQPENNYKTTPPVLDSDGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTG SFFLYSKLTVDKSRWQQGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAA GNVFSCSVMHEALHNHYCTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA TQKSLSLSPGK (SEQ IDAGACAAAGCCGTGCGAGGAGCAGTACGGCAGCACG NO: 532)TACCGTTGCGTCAGCGTCCTCACCGTCCTGCACCAG GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAA CCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGAT GACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGG GAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCT TCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATG CATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA (SEQ ID NO: 565) 3575 HC-12 QVQLQQSGPGLVKPSQTLCAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGT SLTCAISGDSVSSNSATWGAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCAT NWIRQSPSRGLEWLGRTYCTCCGGGGACAGTGTCTCTAGCAACAGTGCTACTTG YRSKWSNHYAVSVKSRITGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTG INPDTSKSQFSLQLNSVTPAGTGGCTGGGAAGGACATATTACAGGTCCAAGTGG EDTAVYYCARGTWKQLTCTAATCATTATGCAGTATCTGTGAAAAGTCGAATC WFLDHWGQGTLVTVSSAACCATCAACCCCGACACGTCCAAGAGCCAGTTCTCC STKGPSVFPLAPSSKSTSGCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCT GTAALGCLVKDYFPEPVTGTGTATTACTGTGCAAGAGGAACGTGGAAACAGCT VSWNSGALTSGVHTFPAATGGTTCCTTGACCACTGGGGCCAGGGAACCCTGGT VLQSSGLYSLSSVVTVPSSCACCGTGTCTAGTGCCTCCACCAAGGGCCCATCGGT SLGTQTYICNVNHKPSNTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGG KVDKKVEPKSCDKTHTCGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACT PPCPAPELLGGPSVFLFPPACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCA KPKDTLMISRTPEVTCVVGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCT VDVSHEDPEVKFNWYVDGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGC GVEVHNAKTKPCEEQYGGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA STYRCVSVLTVLHQDWLGACCTACATCTGCAACGTGAATCACAAGCCCAGCA NGKEYKCKVSNKALPAPIACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCT EKTISKAKGQPREPQVYTTGTGACAAAACTCACACATGCCCACCGTGCCCAGC LPPSREEMTKNQVSLTCLACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTT VKGFYPSDIAVEWESNGQCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCG PENNYKTTPPVLDSDGSFGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGA FLYSKLTVDKSRWQQGNGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTAC VFSCSVMHEALHNHYTQGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA KSLSLSPGK (SEQ ID NO:GCCGTGCGAGGAGCAGTACGGCAGCACGTACCGTT 530)GCGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGC TGAATGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTC CAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAG AACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAA TGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATA GCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCT CTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGCAAA (SEQ ID NO: 563)

In certain embodiments, the anti-PAC1 antibodies of the invention maycomprise a light chain selected from LC-01 to LC-05, as shown in Table4A, and/or a heavy chain selected from HC-01 to HC-11, as shown in Table4B, and binding fragments, derivatives, and variants of these lightchains and heavy chains. In other embodiments, the anti-PAC1 antibodiesof the invention may comprise a light chain selected from LC-06 toLC-15, as shown in Table 4A, and/or a heavy chain selected from HC-12 toHC-18, as shown in Table 4B, and binding fragments, derivatives, andvariants of these light chains and heavy chains.

Each of the light chains listed in Table 4A may be combined with any ofthe heavy chains listed in Table 4B to form an anti-PAC1 antibody orantigen-binding fragment thereof of the invention. For example, incertain embodiments, the anti-PAC1 antibodies of the invention comprisea light chain comprising the sequence of LC-03 (SEQ ID NO: 506) and aheavy chain comprising the sequence of HC-03 (SEQ ID NO: 521). In someembodiments, the anti-PAC1 antibodies of the invention comprise a lightchain comprising the sequence of LC-03 (SEQ ID NO: 506) and a heavychain comprising the sequence of HC-04 (SEQ ID NO: 522). In otherembodiments, the anti-PAC1 antibodies of the invention comprise a lightchain comprising the sequence of LC-01 (SEQ ID NO: 504) and a heavychain comprising the sequence of HC-05 (SEQ ID NO: 523). In still otherembodiments, the anti-PAC1 antibodies of the invention comprise a lightchain comprising the sequence of LC-01 (SEQ ID NO: 504) and a heavychain comprising the sequence of HC-06 (SEQ ID NO: 524). In someembodiments, the anti-PAC1 antibodies of the invention comprise a lightchain comprising the sequence of LC-03 (SEQ ID NO: 506) and a heavychain comprising the sequence of HC-07 (SEQ ID NO: 525). In certainembodiments, the anti-PAC1 antibodies of the invention comprise a lightchain comprising the sequence of LC-01 (SEQ ID NO: 504) and a heavychain comprising the sequence of HC-08 (SEQ ID NO: 526). In oneembodiment, the anti-PAC1 antibodies of the invention comprise a lightchain comprising the sequence of LC-03 (SEQ ID NO: 506) and a heavychain comprising the sequence of HC-05 (SEQ ID NO: 523). In anotherembodiment, the anti-PAC1 antibodies of the invention comprise a lightchain comprising the sequence of LC-04 (SEQ ID NO: 507) and a heavychain comprising the sequence of HC-09 (SEQ ID NO: 527). In yet anotherembodiment, the anti-PAC1 antibodies of the invention comprise a lightchain comprising the sequence of LC-04 (SEQ ID NO: 507) and a heavychain comprising the sequence of HC-10 (SEQ ID NO: 528). In stillanother embodiment, the anti-PAC1 antibodies of the invention comprise alight chain comprising the sequence of LC-05 (SEQ ID NO: 508) and aheavy chain comprising the sequence of HC-11 (SEQ ID NO: 529).

In certain other embodiments, the anti-PAC1 antibodies of the inventioncomprise a light chain comprising the sequence of LC-07 (SEQ ID NO: 510)and a heavy chain comprising the sequence of HC-13 (SEQ ID NO: 531). Insome embodiments, the anti-PAC1 antibodies of the invention comprise alight chain comprising the sequence of LC-08 (SEQ ID NO: 511) and aheavy chain comprising the sequence of HC-14 (SEQ ID NO: 532). In otherembodiments, the anti-PAC1 antibodies of the invention comprise a lightchain comprising the sequence of LC-09 (SEQ ID NO: 512) and a heavychain comprising the sequence of HC-15 (SEQ ID NO: 533). In still otherembodiments, the anti-PAC1 antibodies of the invention comprise a lightchain comprising the sequence of LC-10 (SEQ ID NO: 513) and a heavychain comprising the sequence of HC-16 (SEQ ID NO: 534). In someembodiments, the anti-PAC1 antibodies of the invention comprise a lightchain comprising the sequence of LC-11 (SEQ ID NO: 514) and a heavychain comprising the sequence of HC-17 (SEQ ID NO: 535). In certainembodiments, the anti-PAC1 antibodies of the invention comprise a lightchain comprising the sequence of LC-12 (SEQ ID NO: 515) and a heavychain comprising the sequence of HC-17 (SEQ ID NO: 535). In oneembodiment, the anti-PAC1 antibodies of the invention comprise a lightchain comprising the sequence of LC-13 (SEQ ID NO: 516) and a heavychain comprising the sequence of HC-14 (SEQ ID NO: 532). In anotherembodiment, the anti-PAC1 antibodies of the invention comprise a lightchain comprising the sequence of LC-14 (SEQ ID NO: 517) and a heavychain comprising the sequence of HC-18 (SEQ ID NO: 536). In yet anotherembodiment, the anti-PAC1 antibodies of the invention comprise a lightchain comprising the sequence of LC-06 (SEQ ID NO: 509) and a heavychain comprising the sequence of HC-14 (SEQ ID NO: 532). In stillanother embodiment, the anti-PAC1 antibodies of the invention comprise alight chain comprising the sequence of LC-15 (SEQ ID NO: 518) and aheavy chain comprising the sequence of HC-12 (SEQ ID NO: 530).

In some embodiments, the anti-PAC1 antibodies comprise a light chaincomprising a sequence of contiguous amino acids that differs from thesequence of a light chain in Table 4A, i.e. a light chain selected fromLC-01 to LC-15, at only 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or15 amino acid residues, wherein each such sequence difference isindependently either a deletion, insertion or substitution of one aminoacid, with the deletions, insertions and/or substitutions resulting inno more than 15 amino acid changes relative to the foregoing light chainsequences. The light chain in some anti-PAC1 antibodies comprises asequence of amino acids that has at least 70%, at least 75%, at least80%, at least 85%, at least 90%, at least 95%, at least 97% or at least99% sequence identity to the amino acid sequences of SEQ ID NOs: 504 to518 (i.e. the light chains in Table 4A).

In these and other embodiments, the anti-PAC1 antibodies comprise aheavy chain comprising a sequence of contiguous amino acids that differsfrom the sequence of a heavy chain in Table 4B, i.e., a heavy chainselected from HC-01 to HC-18, at only 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14 or 15 amino acid residues, wherein each such sequencedifference is independently either a deletion, insertion or substitutionof one amino acid, with the deletions, insertions and/or substitutionsresulting in no more than 15 amino acid changes relative to theforegoing heavy chain sequences. The heavy chain in some anti-PAC1antibodies comprises a sequence of amino acids that has at least 70%, atleast 75%, at least 80%, at least 85%, at least 90%, at least 95%, atleast 97% or at least 99% sequence identity to the amino acid sequencesof SEQ ID NOs: 519 to 536 (i.e. the heavy chains in Table 4B).

The anti-PAC1 antibodies or antigen-binding fragments of the inventioncan be monoclonal antibodies, polyclonal antibodies, recombinantantibodies, human antibodies, humanized antibodies, chimeric antibodies,or multispecific antibodies or antigen-binding fragments thereof. Incertain embodiments, the anti-PAC1 antibody is a monoclonal antibody. Insuch embodiments, the anti-PAC1 antibody may be a chimeric antibody, ahumanized antibody, or a fully human antibody having a humanimmunoglobulin constant domain. In these and other embodiments, theanti-PAC1 antibody is a human IgG1, IgG2, IgG3, or IgG4 antibody. Thus,the anti-PAC1 antibody may, in some embodiments, have a human IgG1,IgG2, IgG3, or IgG4 constant domain. In one embodiment, the anti-PAC1antibody is a monoclonal human IgG1 antibody. In another embodiment, theanti-PAC1 antibody is a monoclonal human IgG2 antibody. In yet anotherembodiment, the anti-PAC1 antibody is a monoclonal human IgG4 antibody.

The term “monoclonal antibody” (or “mAb”) as used herein refers to anantibody obtained from a population of substantially homogeneousantibodies, i.e., the individual antibodies comprising the populationare identical except for possible naturally occurring mutations that maybe present in minor amounts. Monoclonal antibodies are highly specific,being directed against an individual antigenic site or epitope, incontrast to polyclonal antibody preparations that typically includedifferent antibodies directed against different epitopes. Monoclonalantibodies may be produced using any technique known in the art, e.g.,by immortalizing spleen cells harvested from an animal after completionof the immunization schedule. The spleen cells can be immortalized usingany technique known in the art, e.g., by fusing them with myeloma cellsto produce hybridomas. See, for example, Antibodies; Harlow and Lane,Cold Spring Harbor Laboratory Press, 1st Edition, e.g. from 1988, or 2ndEdition, e.g. from 2014. Myeloma cells for use in hybridoma-producingfusion procedures preferably are non-antibody-producing, have highfusion efficiency, and enzyme deficiencies that render them incapable ofgrowing in certain selective media, which support the growth of only thedesired fused cells (hybridomas). Examples of suitable cell lines foruse in fusions with mouse cells include, but are not limited to, Sp-20,P3-X63/Ag8, P3-X63-Ag8.653, NS1/1.Ag 4 1, Sp210-Ag14, FO, NSO/U, MPC-11,MPC11-X45-GTG 1.7 and S194/5XXO Bul. Examples of suitable cell linesused for fusions with rat cells include, but are not limited to,R210.RCY3, Y3-Ag 1.2.3, IR983F and 4B210. Other cell lines useful forcell fusions are U-266, GM1500-GRG2, LICR-LON-HMy2 and UC729-6.

In some instances, a hybridoma cell line is produced by immunizing ananimal (e.g., a rabbit, rat, mouse, or a transgenic animal having humanimmunoglobulin sequences) with a PAC1 immunogen (see, e.g., WO2014/144632); harvesting spleen cells from the immunized animal; fusingthe harvested spleen cells to a myeloma cell line, thereby generatinghybridoma cells; establishing hybridoma cell lines from the hybridomacells, and identifying a hybridoma cell line that produces an antibodythat binds to PAC1. Another useful method for producing monoclonalantibodies is the SLAM method described in Babcook et al., Proc. Natl.Acad. Sci. USA, Vol. 93: 7843-7848, 1996.

Monoclonal antibodies secreted by a hybridoma cell line can be purifiedusing any technique known in the art, such as protein A-Sepharose,hydroxyapatite chromatography, gel electrophoresis, dialysis, oraffinity chromatography. Hybridoma supernatants or mAbs may be furtherscreened to identify mAbs with particular properties, such as theability to bind PAC1 (e.g. human PAC1, cynomolgus monkey PAC1, or ratPAC1); cross-reactivity to other PAC1 family members (e.g. human VPAC1or human VPAC2); ability to block or interfere with the binding of thePACAP ligand to PAC1, or the ability to functionally block PACAP-inducedactivation of the PAC1 receptor, e.g., using a cAMP assay as describedherein.

In some embodiments, the anti-PAC1 antibodies or antigen-bindingfragments of the invention are chimeric or humanized antibodies orantigen-binding fragments thereof based upon the CDR and variable regionsequences of the antibodies described herein. A chimeric antibody is anantibody composed of protein segments from different antibodies that arecovalently joined to produce functional immunoglobulin light or heavychains or binding fragments thereof. Generally, a portion of the heavychain and/or light chain is identical with or homologous to acorresponding sequence in antibodies derived from a particular speciesor belonging to a particular antibody class or subclass, while theremainder of the chain(s) is/are identical with or homologous to acorresponding sequence in antibodies derived from another species orbelonging to another antibody class or subclass. For methods relating tochimeric antibodies, see, for example, U.S. Pat. No. 4,816,567 andMorrison et al., 1985, Proc. Natl. Acad. Sci. USA 81:6851-6855, both ofwhich are hereby incorporated by reference in their entireties.

Generally, the goal of making a chimeric antibody is to create a chimerain which the number of amino acids from the intended species ismaximized. One example is the “CDR-grafted” antibody, in which theantibody comprises one or more CDRs from a particular species orbelonging to a particular antibody class or subclass, while theremainder of the antibody chain(s) is/are identical with or homologousto a corresponding sequence in antibodies derived from another speciesor belonging to another antibody class or subclass. CDR grafting isdescribed, for example, in U.S. Pat. Nos. 6,180,370, 5,693,762,5,693,761, 5,585,089, and 5,530,101. For use in humans, the variableregion or selected CDRs from a rodent or rabbit antibody often aregrafted into a human antibody, replacing the naturally-occurringvariable regions or CDRs of the human antibody.

One useful type of chimeric antibody is a “humanized” antibody.Generally, a humanized antibody is produced from a monoclonal antibodyraised initially in a non-human animal, such as a rodent or rabbit.Certain amino acid residues in this monoclonal antibody, typically fromnon-antigen recognizing portions of the antibody, are modified to behomologous to corresponding residues in a human antibody ofcorresponding isotype. Humanization can be performed, for example, usingvarious methods by substituting at least a portion of a rodent or rabbitvariable region for the corresponding regions of a human antibody (see,e.g., U.S. Pat. Nos. 5,585,089, and 5,693,762; Jones et al., 1986,Nature 321:522-525; Riechmann et al., 1988, Nature 332:323-27; andVerhoeyen et al., 1988, Science 239:1534-1536).

In one aspect, the CDRs of the light and heavy chain variable regions ofthe antibodies provided herein (see, Tables 1A and 1B) are grafted toframework regions (FRs) from antibodies from the same, or a different,phylogenetic species. For example, the CDRs of the heavy and light chainvariable regions listed in Tables 1A and 1B can be grafted to consensushuman FRs. To create consensus human FRs, FRs from several human heavychain or light chain amino acid sequences may be aligned to identify aconsensus amino acid sequence. Alternatively, the grafted variableregions from the one heavy or light chain may be used with a constantregion that is different from the constant region of that particularheavy or light chain as disclosed herein. In other embodiments, thegrafted variable regions are part of a single chain Fv antibody.

In certain embodiments, the anti-PAC1 antibodies or antigen-bindingfragments of the invention are fully human antibodies or antigen-bindingfragments thereof. Fully human antibodies that specifically bind tohuman PAC1 can be generated using the immunogens or fragments thereofdescribed in WO 2014/144632, such as polypeptides consisting of thesequence of SEQ ID NO: 1 or SEQ ID NO: 4. A “fully human antibody” is anantibody that comprises variable and constant regions derived from orindicative of human germ line immunoglobulin sequences. One specificmeans provided for implementing the production of fully human antibodiesis the “humanization” of the mouse humoral immune system. Introductionof human immunoglobulin (Ig) loci into mice in which the endogenous Iggenes have been inactivated is one means of producing fully humanmonoclonal antibodies (mAbs) in mouse, an animal that can be immunizedwith any desirable antigen. Using fully human antibodies can minimizethe immunogenic and allergic responses that can sometimes be caused byadministering mouse or mouse-derived mAbs to humans as therapeuticagents.

Fully human antibodies can be produced by immunizing transgenic animals(usually mice) that are capable of producing a repertoire of humanantibodies in the absence of endogenous immunoglobulin production.Antigens for this purpose typically have six or more contiguous aminoacids, and optionally are conjugated to a carrier, such as a hapten.See, e.g., Jakobovits et al., 1993, Proc. Natl. Acad. Sci. USA90:2551-2555; Jakobovits et al., 1993, Nature 362:255-258; andBruggermann et al., 1993, Year in Immunol. 7:33. In one example of sucha method, transgenic animals are produced by incapacitating theendogenous mouse immunoglobulin loci encoding the mouse heavy and lightimmunoglobulin chains therein, and inserting into the mouse genome largefragments of human genome DNA containing loci that encode human heavyand light chain proteins. Partially modified animals, which have lessthan the full complement of human immunoglobulin loci, are thencross-bred to obtain an animal having all of the desired immune systemmodifications. When administered an immunogen, these transgenic animalsproduce antibodies that are immunospecific for the immunogen but havehuman rather than murine amino acid sequences, including the variableregions. For further details of such methods, see, for example,WO96/33735 and WO94/02602. Additional methods relating to transgenicmice for making human antibodies are described in U.S. Pat. Nos.5,545,807; 6,713,610; 6,673,986; 6,162,963; 5,939,598; 5,545,807;6,300,129; 6,255,458; 5,877,397; 5,874,299 and 5,545,806; in PCTpublications WO91/10741, WO90/04036, WO 94/02602, WO 96/30498, WO98/24893 and in EP 546073B1 and EP 546073A1.

The transgenic mice described above, referred to as “HuMab” mice,contain a human immunoglobulin gene minilocus that encodes unrearrangedhuman heavy (mu and gamma) and kappa light chain immunoglobulinsequences, together with targeted mutations that inactivate theendogenous mu and kappa chain loci (Lonberg et al., 1994, Nature368:856-859). Accordingly, the mice exhibit reduced expression of mouseIgM and kappa proteins and in response to immunization, the introducedhuman heavy and light chain transgenes undergo class switching andsomatic mutation to generate high affinity human IgG kappa monoclonalantibodies (Lonberg and Huszar, 1995, Intern. Rev. Immunol. 13: 65-93;Harding and Lonberg, 1995, Ann. N.Y Acad. Sci. 764:536-546). Thepreparation of HuMab mice is described in detail in Taylor et al., 1992,Nucleic Acids Research 20:6287-6295; Chen et al., 1993, InternationalImmunology 5:647-656; Tuaillon et al., 1994, J. Immunol. 152:2912-2920;Lonberg et al., 1994, Nature 368:856-859; Lonberg, 1994, Handbook ofExp. Pharmacology 113:49-101; Taylor et al., 1994, InternationalImmunology 6:579-591; Lonberg and Huszar, 1995, Intern. Rev. Immunol.13:65-93; Harding and Lonberg, 1995, Ann. N.Y Acad. Sci. 764:536-546;Fishwild et al., 1996, Nature Biotechnology 14:845-851; the foregoingreferences are hereby incorporated by reference in their entireties.See, further U.S. Pat. Nos. 5,545,806; 5,569,825; 5,625,126; 5,633,425;5,789,650; 5,877,397; 5,661,016; 5,814,318; 5,874,299; and 5,770,429; aswell as U.S. Pat. No. 5,545,807; International Publication Nos. WO93/1227; WO 92/22646; and WO 92/03918, the disclosures of all of whichare hereby incorporated by reference in their entireties. Technologiesutilized for producing human antibodies in these transgenic mice aredisclosed also in WO 98/24893, and Mendez et al., 1997, Nature Genetics15:146-156, which are hereby incorporated by reference. For example, theHCo7 and HCol2 transgenic mice strains can be used to generate fullyhuman anti-PAC1 antibodies. One particular transgenic mouse linesuitable for generation of fully human anti-PAC1 antibodies is theXenoMouse® transgenic mouse line described in U.S. Pat. Nos. 6,114,598;6,162,963; 6,833,268; 7,049,426; 7,064,244; Green et al., 1994, NatureGenetics 7:13-21; Mendez et al., 1997, Nature Genetics 15:146-156; Greenand Jakobovitis, 1998, J. Ex. Med, 188:483-495; Green, 1999, Journal ofImmunological Methods 231:11-23; Kellerman and Green, 2002, CurrentOpinion in Biotechnology 13, 593-597, all of which are herebyincorporated by reference in their entireties.

Human-derived antibodies can also be generated using phage displaytechniques. Phage display is described in e.g., Dower et al., WO91/17271, McCafferty et al., WO 92/01047, and Caton and Koprowski, 1990,Proc. Natl. Acad. Sci. USA, 87:6450-6454, each of which is incorporatedherein by reference in its entirety. The antibodies produced by phagetechnology are usually produced as antigen-binding fragments, e.g. Fv orFab fragments, in bacteria and thus lack effector functions. Effectorfunctions can be introduced by one of two strategies: The fragments canbe engineered either into complete antibodies for expression inmammalian cells, or into bispecific antibody fragments with a secondbinding site capable of triggering an effector function, if desired.Typically, the Fd fragment (VH-CH1) and light chain (VL-CL) ofantibodies are separately cloned by PCR and recombined randomly incombinatorial phage display libraries, which can then be selected forbinding to a particular antigen. The antibody fragments are expressed onthe phage surface, and selection of Fv or Fab (and therefore the phagecontaining the DNA encoding the antibody fragment) by antigen binding isaccomplished through several rounds of antigen binding andre-amplification, a procedure termed panning. Antibody fragmentsspecific for the antigen are enriched and finally isolated. Phagedisplay techniques can also be used in an approach for the humanizationof rodent monoclonal antibodies, called “guided selection” (see Jespers,L. S. et al., 1994, Bio/Technology 12, 899-903). For this, the Fdfragment of the mouse monoclonal antibody can be displayed incombination with a human light chain library, and the resulting hybridFab library may then be selected with antigen. The mouse Fd fragmentthereby provides a template to guide the selection. Subsequently, theselected human light chains are combined with a human Fd fragmentlibrary. Selection of the resulting library yields entirely human Fab.

Once cells producing anti-PAC1 antibodies according to the inventionhave been obtained using any of the above described immunization andother techniques, the specific antibody genes may be cloned by isolatingand amplifying DNA or mRNA therefrom according to standard procedures asdescribed herein. The antibodies produced therefrom may be sequenced andthe CDRs identified and the DNA coding for the CDRs may be manipulatedas described herein to generate other anti-PAC1 antibodies orantigen-binding fragments according to the invention.

In certain embodiments, the anti-PAC1 antibodies and antigen-bindingfragments of the invention may comprise one or more mutations ormodifications to a constant region. For example, the heavy chainconstant regions or the Fc regions of the anti-PAC1 antibodies maycomprise one or more amino acid substitutions that affect theglycosylation, effector function, and/or Fcγ receptor binding of theantibody. The term “Fc region” refers to the C-terminal region of animmunoglobulin heavy chain, which may be generated by papain digestionof an intact antibody. The Fc region of an immunoglobulin generallycomprises two constant domains, a CH2 domain and a CH3 domain, andoptionally comprises a CH4 domain. In certain embodiments, the Fc regionis an Fc region from an IgG1, IgG2, IgG3, or IgG4 immunoglobulin. Insome embodiments, the Fc region comprises CH2 and CH3 domains from ahuman IgG1 or human IgG2 immunoglobulin. The Fc region may retaineffector function, such as C1q binding, complement-dependentcytotoxicity (CDC), Fc receptor binding, antibody-dependentcell-mediated cytotoxicity (ADCC), and phagocytosis. In otherembodiments, the Fc region may be modified to reduce or eliminateeffector function as described in further detail below.

Unless indicated otherwise by reference to a specific sequence,throughout the present specification and claims, the numbering of theamino acid residues in an immunoglobulin heavy chain or light chain isaccording to AHo numbering as described in Honegger and Pluckthun, J.Mol. Biol. 309(3):657-670; 2001 or EU numbering as described in Edelmanet al., Proc. Natl. Acad. USA, Vol. 63: 78-85 (1969). As used herein,the AHo numbering scheme is typically used when referring to theposition of an amino acid within the variable regions, whereas the EUnumbering scheme is generally used when referring to the position of anamino acid with an immunoglobulin constant region.

An amino acid substitution in an amino acid sequence is typicallydesignated herein with a one-letter abbreviation for the amino acidresidue in a particular position, followed by the numerical amino acidposition relative to an original sequence of interest, which is thenfollowed by the one-letter abbreviation for the amino acid residuesubstituted in. For example, “T30D” symbolizes a substitution of athreonine residue by an aspartate residue at amino acid position 30,relative to the original sequence of interest. Another example, “5218G”symbolizes a substitution of a serine residue by a glycine residue atamino acid position 218, relative to the original amino acid sequence ofinterest.

One of the functions of the Fc region of an immunoglobulin is tocommunicate to the immune system when the immunoglobulin binds itstarget. This is commonly referred to as “effector function.”Communication leads to antibody-dependent cellular cytotoxicity (ADCC),antibody-dependent cellular phagocytosis (ADCP), and/or complementdependent cytotoxicity (CDC). ADCC and ADCP are mediated through thebinding of the Fc region to Fc receptors on the surface of cells of theimmune system. CDC is mediated through the binding of the Fc region withproteins of the complement system, e.g., C1q. In some embodiments, theanti-PAC1 antibodies of the invention comprise one or more amino acidsubstitutions in the Fc region to enhance effector function, includingADCC activity, CDC activity, ADCP activity, and/or the clearance orhalf-life of the antibody. Exemplary amino acid substitutions (accordingto the EU numbering scheme) that can enhance effector function include,but are not limited to, E233L, L2341, L234Y, L235S, G236A, S239D, F243L,F243V, P247I, D280H, K290S, K290E, K290N, K290Y, R292P, E294L, Y296W,S298A, S298D, S298V, S298G, S298T, T299A, Y300L, V3051, Q311M, K326A,K326E, K326W, A330S, A330L, A330M, A330F, I332E, D333A, E333S, E333A,K334A, K334V, A339D, A339Q, P396L, or combinations of any of theforegoing.

In other embodiments, the anti-PAC1 antibodies of the invention compriseone or more amino acid substitutions in the Fc region to reduce effectorfunction. Exemplary amino acid substitutions (according to the EUnumbering scheme) that can reduce effector function include, but are notlimited to, C220S, C226S, C229S, E233P, L234A, L234V, V234A, L234F,L235A, L235E, G237A, P238S, S267E, H268Q, N297A, N297G, V309L, E318A,L328F, A330S, A331S, P331S, or combinations of any of the foregoing.

Glycosylation can contribute to the effector function of antibodies,particularly IgG1 antibodies. Thus, in some embodiments, the anti-PAC1antibodies of the invention may comprise one or more amino acidsubstitutions that affect the level or type of glycosylation of theantibodies. Glycosylation of polypeptides is typically either N-linkedor O-linked. N-linked refers to the attachment of the carbohydratemoiety to the side chain of an asparagine residue. The tri-peptidesequences asparagine-X-serine and asparagine-X-threonine, where X is anyamino acid except proline, are the recognition sequences for enzymaticattachment of the carbohydrate moiety to the asparagine side chain.Thus, the presence of either of these tri-peptide sequences in apolypeptide creates a potential glycosylation site. O-linkedglycosylation refers to the attachment of one of the sugarsN-acetylgalactosamine, galactose, or xylose, to a hydroxyamino acid,most commonly serine or threonine, although 5-hydroxyproline or5-hydroxylysine may also be used.

In certain embodiments, glycosylation of the anti-PAC1 antibodiesdescribed herein is increased by adding one or more glycosylation sites,e.g., to the Fc region of the antibody. Addition of glycosylation sitesto the antibody can be conveniently accomplished by altering the aminoacid sequence such that it contains one or more of the above-describedtri-peptide sequences (for N-linked glycosylation sites). The alterationmay also be made by the addition of, or substitution by, one or moreserine or threonine residues to the starting sequence (for O-linkedglycosylation sites). For ease, the antibody amino acid sequence may bealtered through changes at the DNA level, particularly by mutating theDNA encoding the target polypeptide at preselected bases such thatcodons are generated that will translate into the desired amino acids.

The invention also encompasses production of antibody molecules withaltered carbohydrate structure resulting in altered effector activity,including antibodies with absent or reduced fucosylation that exhibitimproved ADCC activity. Various methods are known in the art to reduceor eliminate fucosylation. For example, ADCC effector activity ismediated by binding of the antibody molecule to the FcγRIII receptor,which has been shown to be dependent on the carbohydrate structure ofthe N-linked glycosylation at the N297 residue of the CH2 domain.Non-fucosylated antibodies bind this receptor with increased affinityand trigger FcγRIII-mediated effector functions more efficiently thannative, fucosylated antibodies. For example, recombinant production ofnon-fucosylated antibody in CHO cells in which the alpha-1,6-fucosyltransferase enzyme has been knocked out results in antibody with100-fold increased ADCC activity (see Yamane-Ohnuki et al., BiotechnolBioeng. 87(5):614-22, 2004). Similar effects can be accomplished throughdecreasing the activity of alpha-1,6-fucosyl transferase enzyme or otherenzymes in the fucosylation pathway, e.g., through siRNA or antisenseRNA treatment, engineering cell lines to knockout the enzyme(s), orculturing with selective glycosylation inhibitors (see Rothman et al.,Mol Immunol. 26(12):1113-23, 1989). Some host cell strains, e.g. Lec13or rat hybridoma YB2/0 cell line naturally produce antibodies with lowerfucosylation levels (see Shields et al., J Biol Chem. 277(30):26733-40,2002 and Shinkawa et al., J Biol Chem. 278(5):3466-73, 2003). Anincrease in the level of bisected carbohydrate, e.g. throughrecombinantly producing antibody in cells that overexpress GnTIIIenzyme, has also been determined to increase ADCC activity (see Umana etal., Nat Biotechnol. 17(2):176-80, 1999).

In other embodiments, glycosylation of the anti-PAC1 antibodiesdescribed herein is decreased or eliminated by removing one or moreglycosylation sites, e.g., from the Fc region of the antibody. In someembodiments, the anti-PAC1 antibody is an aglycosylated human monoclonalantibody, e.g., an aglycosylated human IgG1 monoclonal antibody. Aminoacid substitutions that eliminate or alter N-linked glycosylation sitescan reduce or eliminate N-linked glycosylation of the antibody. Incertain embodiments, the anti-PAC1 antibodies described herein comprisea heavy chain mutation at position N297 (according to the EU numberingscheme), such as N297Q, N297A, or N297G. In some embodiments, theanti-PAC1 antibodies of the invention comprise an Fc region from a humanIgG1 antibody with a mutation at position N297. In one particularembodiment, the anti-PAC1 antibodies of the invention comprise an Fcregion from a human IgG1 antibody with a N297G mutation. For instance,in some embodiments, the anti-PAC1 antibodies of the invention comprisea heavy chain constant region comprising the sequence of SEQ ID NO: 324.

To improve the stability of molecules comprising a N297 mutation, the Fcregion of the anti-PAC1 antibodies may be further engineered. Forinstance, in some embodiments, one or more amino acids in the Fc regionare substituted with cysteine to promote disulfide bond formation in thedimeric state. Residues corresponding to V259, A287, R292, V302, L306,V323, or 1332 (according to the EU numbering scheme) of an IgG1 Fcregion may thus be substituted with cysteine. Preferably, specific pairsof residues are substituted with cysteine such that they preferentiallyform a disulfide bond with each other, thus limiting or preventingdisulfide bond scrambling. Preferred pairs include, but are not limitedto, A287C and L306C, V259C and L306C, R292C and V302C, and V323C andI332C. In certain embodiments, the anti-PAC1 antibodies described hereincomprise an Fc region from a human IgG1 antibody with mutations R292Cand V302C. In such embodiments, the Fc region may also comprise a N297mutation, such as a N297G mutation. In some embodiments, the anti-PAC1antibodies of the invention comprise a heavy chain constant regioncomprising the sequence of SEQ ID NO: 325.

Modifications of the anti-PAC1 antibodies of the invention to increaseserum half-life also may desirable, for example, by incorporation of oraddition of a salvage receptor binding epitope (e.g., by mutation of theappropriate region or by incorporating the epitope into a peptide tagthat is then fused to the antibody at either end or in the middle, e.g.,by DNA or peptide synthesis; see, e.g., WO96/32478) or adding moleculessuch as PEG or other water soluble polymers, including polysaccharidepolymers. The salvage receptor binding epitope preferably constitutes aregion wherein any one or more amino acid residues from one or two loopsof an Fc region are transferred to an analogous position in theantibody. Even more preferably, three or more residues from one or twoloops of the Fc region are transferred. Still more preferred, theepitope is taken from the CH2 domain of the Fc region (e.g., an IgG Fcregion) and transferred to the CH1, CH3, or VH region, or more than onesuch region, of the antibody. Alternatively, the epitope is taken fromthe CH2 domain of the Fc region and transferred to the CL region or VLregion, or both, of the antibody. See International applications WO97/34631 and WO 96/32478 for a description of Fc variants and theirinteraction with the salvage receptor.

The present invention includes one or more isolated polynucleotides orisolated nucleic acids encoding the anti-PAC1 antibodies orantigen-binding fragments described herein. In addition, the presentinvention encompasses vectors comprising the nucleic acids, host cellsor cell lines comprising the nucleic acids, and methods of making theanti-PAC1 antibodies and antigen-binding fragments of the invention. Thenucleic acids comprise, for example, polynucleotides that encode all orpart of an antibody or antigen-binding fragment, for example, one orboth chains of an antibody of the invention, or a fragment, derivative,or variant thereof, polynucleotides sufficient for use as hybridizationprobes, PCR primers or sequencing primers for identifying, analyzing,mutating or amplifying a polynucleotide encoding a polypeptide,antisense oligonucleotides for inhibiting expression of apolynucleotide, and complementary sequences of the foregoing. Thenucleic acids can be any length as appropriate for the desired use orfunction, and can comprise one or more additional sequences, forexample, regulatory sequences, and/or be part of a larger nucleic acid,for example, a vector. Nucleic acid molecules of the invention includeDNA and RNA in both single-stranded and double-stranded form, as well asthe corresponding complementary sequences. DNA includes, for example,cDNA, genomic DNA, chemically synthesized DNA, DNA amplified by PCR, andcombinations thereof. The nucleic acid molecules of the inventioninclude full-length genes or cDNA molecules as well as a combination offragments thereof. The nucleic acids of the invention can be derivedfrom human sources as well as non-human species.

Relevant amino acid sequences from an immunoglobulin or region thereof(e.g. variable region, Fc region, etc.) or polypeptide of interest maybe determined by direct protein sequencing, and suitable encodingnucleotide sequences can be designed according to a universal codontable. Alternatively, genomic or cDNA encoding monoclonal antibodies orbinding fragments thereof of the invention can be isolated and sequencedfrom cells producing such antibodies using conventional procedures(e.g., by using oligonucleotide probes that are capable of bindingspecifically to genes encoding the heavy and light chains of themonoclonal antibodies).

An “isolated nucleic acid,” which is used interchangeably herein with“isolated polynucleotide,” is a nucleic acid that has been separatedfrom adjacent genetic sequences present in the genome of the organismfrom which the nucleic acid was isolated, in the case of nucleic acidsisolated from naturally-occurring sources. In the case of nucleic acidssynthesized enzymatically from a template or chemically, such as PCRproducts, cDNA molecules, or oligonucleotides for example, it isunderstood that the nucleic acids resulting from such processes areisolated nucleic acids. An isolated nucleic acid molecule refers to anucleic acid molecule in the form of a separate fragment or as acomponent of a larger nucleic acid construct. In one preferredembodiment, the nucleic acids are substantially free from contaminatingendogenous material. The nucleic acid molecule has preferably beenderived from DNA or RNA isolated at least once in substantially pureform and in a quantity or concentration enabling identification,manipulation, and recovery of its component nucleotide sequences bystandard biochemical methods (such as those outlined in Sambrook et al.,Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring HarborLaboratory, Cold Spring Harbor, N.Y. (1989)). Such sequences arepreferably provided and/or constructed in the form of an open readingframe uninterrupted by internal non-translated sequences, or introns,that are typically present in eukaryotic genes. Sequences ofnon-translated DNA can be present 5′ or 3′ from an open reading frame,where the same do not interfere with manipulation or expression of thecoding region. Unless specified otherwise, the left-hand end of anysingle-stranded polynucleotide sequence discussed herein is the 5′ end;the left-hand direction of double-stranded polynucleotide sequences isreferred to as the 5′ direction. The direction of 5′ to 3′ production ofnascent RNA transcripts is referred to as the transcription direction;sequence regions on the DNA strand having the same sequence as the RNAtranscript that are 5′ to the 5′ end of the RNA transcript are referredto as “upstream sequences;” sequence regions on the DNA strand havingthe same sequence as the RNA transcript that are 3′ to the 3′ end of theRNA transcript are referred to as “downstream sequences.”

The present invention also includes nucleic acids that hybridize undermoderately stringent conditions, and more preferably highly stringentconditions, to nucleic acids encoding polypeptides as described herein.The basic parameters affecting the choice of hybridization conditionsand guidance for devising suitable conditions are set forth by Sambrook,Fritsch, and Maniatis (1989, Molecular Cloning: A Laboratory Manual,Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., chapters9 and 11; and Current Protocols in Molecular Biology, 1995, Ausubel etal., eds., John Wiley & Sons, Inc., sections 2.10 and 6.3-6.4), and canbe readily determined by those having ordinary skill in the art basedon, for example, the length and/or base composition of the DNA. One wayof achieving moderately stringent conditions involves the use of aprewashing solution containing 5×SSC, 0.5% SDS, 1.0 mM EDTA (pH 8.0),hybridization buffer of about 50% formamide, 6×SSC, and a hybridizationtemperature of about 55° C. (or other similar hybridization solutions,such as one containing about 50% formamide, with a hybridizationtemperature of about 42° C.), and washing conditions of about 60° C., in0.5×SSC, 0.1% SDS. Generally, highly stringent conditions are defined ashybridization conditions as above, but with washing at approximately 68°C., 0.2×SSC, 0.1% SDS. SSPE (1×SSPE is 0.15M NaCl, 10 mM NaH₂PO₄, and1.25 mM EDTA, pH 7.4) can be substituted for SSC (1×SSC is 0.15M NaCland 15 mM sodium citrate) in the hybridization and wash buffers; washesare performed for 15 minutes after hybridization is complete. It shouldbe understood that the wash temperature and wash salt concentration canbe adjusted as necessary to achieve a desired degree of stringency byapplying the basic principles that govern hybridization reactions andduplex stability, as known to those skilled in the art and describedfurther below (see, e.g., Sambrook et al., 1989).

When hybridizing a nucleic acid to a target nucleic acid of unknownsequence, the hybrid length is assumed to be that of the hybridizingnucleic acid. When nucleic acids of known sequence are hybridized, thehybrid length can be determined by aligning the sequences of the nucleicacids and identifying the region or regions of optimal sequencecomplementarity. The hybridization temperature for hybrids anticipatedto be less than 50 base pairs in length should be 5 to 10° C. less thanthe melting temperature (Tm) of the hybrid, where Tm is determinedaccording to the following equations. For hybrids less than 18 basepairs in length, Tm (° C.)=2(# of A+T bases)+4(# of G+C bases). Forhybrids above 18 base pairs in length, Tm (° C.)=81.5+16.6 (log 10[Na+])+0.41(% G+C)−(600/N), where N is the number of bases in thehybrid, and [Na+] is the concentration of sodium ions in thehybridization buffer ([Na+] for 1×SSC=0.165M). Preferably, each suchhybridizing nucleic acid has a length that is at least 15 nucleotides(or more preferably at least 18 nucleotides, or at least 20 nucleotides,or at least 25 nucleotides, or at least 30 nucleotides, or at least 40nucleotides, or most preferably at least 50 nucleotides), or at least25% (more preferably at least 50%, or at least 60%, or at least 70%, andmost preferably at least 80%) of the length of the nucleic acid of thepresent invention to which it hybridizes, and has at least 60% sequenceidentity (more preferably at least 70%, at least 75%, at least 80%, atleast 81%, at least 82%, at least 83%, at least 84%, at least 85%, atleast 86%, at least 87%, at least 88%, at least 89%, at least 90%, atleast 91%, at least 92%, at least 93%, at least 94%, at least 95%, atleast 96%, at least 97%, at least 98%, or at least 99%, and mostpreferably at least 99.5%) with the nucleic acid of the presentinvention to which it hybridizes, where sequence identity is determinedby comparing the sequences of the hybridizing nucleic acids when alignedso as to maximize overlap and identity while minimizing sequence gaps asdescribed in more detail above.

Variants of the anti-PAC1 antibodies and antigen-binding fragmentsdescribed herein can be prepared by site-specific mutagenesis ofnucleotides in the DNA encoding the polypeptide, using cassette or PCRmutagenesis or other techniques well known in the art, such as thosedescribed in Example 3, to produce DNA encoding the variant, andthereafter expressing the recombinant DNA in cell culture as outlinedherein. However, antibodies or antigen-binding fragments comprisingvariant CDRs having up to about 100-150 residues may be prepared by invitro synthesis using established techniques. The variants typicallyexhibit the same qualitative biological activity as the naturallyoccurring analogue, e.g., binding to antigen. Such variants include, forexample, deletions and/or insertions and/or substitutions of residueswithin the amino acid sequences of the antibodies. Any combination ofdeletion, insertion, and substitution is made to arrive at the finalconstruct, provided that the final construct possesses the desiredcharacteristics. The amino acid changes also may alterpost-translational processes of the antibody, such as changing thenumber or position of glycosylation sites. In certain embodiments,antibody variants are prepared with the intent to modify those aminoacid residues which are directly involved in epitope binding. In otherembodiments, modification of residues which are not directly involved inepitope binding or residues not involved in epitope binding in any way,is desirable, for purposes discussed herein. Mutagenesis within any ofthe CDR regions and/or framework regions is contemplated. Covarianceanalysis techniques can be employed by the skilled artisan to designuseful modifications in the amino acid sequence of the antibody. See,e.g., Choulier, et al., Proteins 41:475-484, 2000; Demarest et al., J.Mol. Biol. 335:41-48, 2004; Hugo et al., Protein Engineering16(5):381-86, 2003; Aurora et al., US Patent Publication No.2008/0318207 A1; Glaser et al., US Patent Publication No. 2009/0048122A1; Urech et al., WO 2008/110348 A1; Borras et al., WO 2009/000099 A2.Such modifications determined by covariance analysis can improvepotency, pharmacokinetic, pharmacodynamic, and/or manufacturabilitycharacteristics of an antibody.

Tables 4A and 4B show exemplary nucleic acid sequences encoding the fulllight and heavy chains, respectively, of anti-PAC1 antibodies describedherein. Tables 5A and 5B show exemplary nucleic acid sequences encodingthe light and heavy chain variable regions, respectively, of anti-PAC1antibodies described herein. Polynucleotides encoding the anti-PAC1variable regions can be used, optionally with nucleic acids encoding thelight and heavy chain constant regions listed in Tables 2 and 3,respectively, to construct the antibodies and antigen-binding fragmentsof the invention.

TABLE 5AExemplary Anti-PAC1 Antibody Light Chain Variable Region Nucleic AcidSequences VL SEQ ID Ab ID. Group VL Nucleic Acid Sequence NO:29G4 variants 29G4v10 LV-01 GAGATCGTACTTACTCAGTCACCCGCCACATTGTCCCT 328GAGCCCGGGTGAACGGGCGACCCTCAGCTGCCGAGCATCCCAGTCCGTCGGACGATCATTGCACTGGTACCAACAAAAACCGGGCCAGGCCCCCAGACTTCTGATCAAGTATGCGTCACAGAGCTTGTCGGGTATTCCCGCTCGCTTTTCGGGGTCGGGATCCGGGACAGATTTCACGCTCACAATCTCCTCGCTGGAACCCGAGGACTTCGCGGTCTACTATTGTCATCAGTCATCGAGGTTGCCTTTCACGTTTGGACCAG GGACCAAGGTGGACATTAAGCGTAC 29G4v22LV-02 GATATCCAGCTCACTCAATCGCCATCATTTCTCTCCGC 329TTCGGTAGGCGACCGGGTCACGATCACATGCAGGGCGTCGCAAAGCATTGGGAGGTCGTTGCATTGGTATCAGCAGAAACCCGGAAAGGCCCCGAAACTTCTGATCAAATACGCATCACAAAGCTTGAGCGGTGTGCCGTCGCGCTTCTCCGGTTCCGGAAGCGGAACGGAATTCACGCTTACAATCTCCTCACTGCAGCCCGAGGATTTCGCGACCTATTACTGTCACCAGTCATCCAGACTCCCGTTTACTTTTGGCCCT GGGACCAAGGTGGACATTAAGCGTACiPS: 420649; iPS: 420653; LV-03 GAGATCGTACTTACTCAGTCACCCGCCACATTGTCCCT330 iPS: 420657; iPS: 420661; GAGCCCGGGTGAACGGGCGACCCTCAGCTGCCGAGCAiPS: 420665; iPS: 420672; TCCAAGTCCGTCGGACGATCATTGCACTGGTACCAACAiPS: 420679; iPS: 420686; AAAACCGGGCCAGGCCCCCAGACTTCTGATCAAGTATiPS: 420837; iPS: 420841; GCGTCACAGAGCTTGTCGGGTATTCCCGCTCGCTTTTCiPS: 420845; iPS: 420849; GGGGTCGGGATCCGGGACAGATTTCACGCTCACAATCiPS: 420853; iPS: 420857; TCCTCGCTGGAACCCGAGGACTTCGCGGTCTACTATTGiPS: 420861; iPS: 420865; TCATCAGTCATCGAGGTTGCCTTTCACGTTTGGACCAGiPS: 420869; iPS: 420873; GGACCAAGGTGGACATTAAG iPS: 420877; iPS: 420881;iPS: 420885; iPS: 420889; iPS: 420893; iPS: 420897;iPS: 421027; iPS: 421031; iPS: 421035; iPS: 421039;iPS: 421043; iPS: 421047; iPS: 421051; iPS: 421055;iPS: 421059; iPS: 421063; iPS: 421067; iPS: 421071;iPS: 421075; iPS: 421079; iPS: 421083; iPS: 421087;iPS: 421147; iPS: 421207; iPS: 421211; iPS: 421215;iPS: 421219; iPS: 421223 iPS: 420690; iPS: 420697; LV-04GAGATCGTACTTACTCAGTCACCCGCCACATTGTCCCT 331 iPS: 420704; iPS: 420711;GAGCCCGGGTGAACGGGCGACCCTCAGCTGCCGAGCA iPS: 420718; iPS: 420725;TCCCAGTCCGTCGGACGATCATTGCACTGGTACCAACA iPS: 420732; iPS: 420739;AAAACCGGGCCAGGCCCCCAGACTTCTGATCAAGTAT iPS: 420746; iPS: 420753;GCGTCACAGAGCTTGTCGGGTATTCCCGCTCGCTTTTC iPS: 420760; iPS: 420767;GGGGTCGGGATCCGGGACAGATTTCACGCTCACAATC iPS: 420774; iPS: 420781;TCCTCGCTGGAACCCGAGGACTTCGCGGTCTACTATTG iPS: 420788; iPS: 420795;TCATCAGTCATCGAGGTTGCCTTTCACGTTTGGACCAG iPS: 420802; iPS: 420809;GGACCAAGGTGGACATTAAG iPS: 420816; iPS: 420823; iPS: 420830; iPS: 420901;iPS: 420908; iPS: 420915; iPS: 420922; iPS: 420929;iPS: 420936; iPS: 420943; iPS: 420950; iPS: 420957;iPS: 420964; iPS: 420971; iPS: 420978; iPS: 420985;iPS: 420992; iPS: 420999; iPS: 421006; iPS: 421013;iPS: 421020; iPS: 421091; iPS: 421098; iPS: 421105;iPS: 421112; iPS: 421119; iPS: 421126; iPS: 421133;iPS: 421140; iPS: 421163; iPS: 391578; iPS: 421170;iPS: 421176; iPS: 421182; iPS: 421239; iPS: 421246;iPS: 421253; iPS: 421260; iPS: 421267; iPS: 421286;iPS: 421293; iPS: 421300; iPS: 421307; iPS: 421326;iPS: 421333; iPS: 421340; iPS: 421347; iPS: 421354;iPS: 421373; iPS: 421380; iPS: 421387; iPS: 421394;iPS: 421855; iPS: 421861; iPS: 421867; iPS: 421873;iPS: 421879; iPS: 421885; iPS: 421891; iPS: 421897;iPS: 421903; iPS: 421909; iPS: 421915 iPS: 421151; iPS: 421227; LV-05GAGATCGTACTTACTCAGTCACCCGCCACATTGTCCCT 332 iPS: 421274; iPS: 421314;GAGCCCGGGTGAACGGGCGACCCTCAGCTGCCGAGCA iPS: 421361TCCCAGTCCGTCTGGCGATCATTGCACTGGTACCAACAAAAACCGGGCCAGGCCCCCAGACTTCTGATCAAGTATGCGTCACAGAGCTTGTCGGGTATTCCCGCTCGCTTTTCGGGGTCGGGATCCGGGACAGATTTCACGCTCACAATCTCCTCGCTGGAACCCGAGGACTTCGCGGTCTACTATTGTCATCAGTCATCGAGGTTGCCTTTCACGTTTGGACCAG GGACCAAGGTGGACATTAAGiPS: 391478; iPS: 421231; LV-06 GAGATCGTACTTACTCAGTCACCCGCCACATTGTCCCT333 iPS: 421278; iPS: 421318; GAGCCCGGGTGAACGGGCGACCCTCAGCTGCCGAGCAiPS: 421365 TCCCAGTCCGTCGGACGAAACTTGCACTGGTACCAACAAAAACCGGGCCAGGCCCCCAGACTTCTGATCAAGTATGCGTCACAGAGCTTGTCGGGTATTCCCGCTCGCTTTTCGGGGTCGGGATCCGGGACAGATTTCACGCTCACAATCTCCTCGCTGGAACCCGAGGACTTCGCGGTCTACTATTGTCATCAGTCATCGAGGTTGCCTTTCACGTTTGGACCA GGGACCAAGGTGGACATTAAGiPS: 421157; iPS: 421235; LV-07 GAGATCGTACTTACTCAGTCACCCGCCACATTGTCCCT334 iPS: 421282; iPS: 421322; GAGCCCGGGTGAACGGGCGACCCTCAGCTGCCGAGCAiPS: 421369 TCCCAGTCCGTCGGACGATCATTGCACTGGTACCAACAAAAACCGGGCCAGGCCCCCAGACTTCTGATCAAGTATGCGTCACAGAGCTTGTCGGGTATTCCCGCTCGCTTTTCGGGGTCGGGATCCGGGACAGATTTCACGCTCACAATCTCCTCGCTGGAACCCGAGGACTTCGCGGTCTACTATTGTCATCAGTCATCGATGTTGCCTTTCACGTTTGGACCAG GGACCAAGGTGGACATTAAG iPS: 421189LV-08 GAGATCGTACTTACTCAGTCACCCGCCACATTGTCCCT 335GAGCCCGGGTGAACGGGCGACCCTCAGCTGCCGAGCATCCAAGTCCGTCTGGCGATCATTGCACTGGTACCAACAAAAACCGGGCCAGGCCCCCAGACTTCTGATCAAGTATGCGTCACAGAGCTTGTCGGGTATTCCCGCTCGCTTTTCGGGGTCGGGATCCGGGACAGATTTCACGCTCACAATCTCCTCGCTGGAACCCGAGGACTTCGCGGTCTACTATTGTCATCAGTCATCGAGGTTGCCTTTCACGTTTGGACCAG GGACCAAGGTGGACATTAAG iPS: 421195LV-09 GAGATCGTACTTACTCAGTCACCCGCCACATTGTCCCT 336GAGCCCGGGTGAACGGGCGACCCTCAGCTGCCGAGCATCCAAGTCCGTCGGACGAAACTTGCACTGGTACCAACAAAAACCGGGCCAGGCCCCCAGACTTCTGATCAAGTATGCGTCACAGAGCTTGTCGGGTATTCCCGCTCGCTTTTCGGGGTCGGGATCCGGGACAGATTTCACGCTCACAATCTCCTCGCTGGAACCCGAGGACTTCGCGGTCTACTATTGTCATCAGTCATCGAGGTTGCCTTTCACGTTTGGACCA GGGACCAAGGTGGACATTAAG iPS: 421201LV-10 GAGATCGTACTTACTCAGTCACCCGCCACATTGTCCCT 337GAGCCCGGGTGAACGGGCGACCCTCAGCTGCCGAGCATCCAAGTCCGTCGGACGATCATTGCACTGGTACCAACAAAAACCGGGCCAGGCCCCCAGACTTCTGATCAAGTATGCGTCACAGAGCTTGTCGGGTATTCCCGCTCGCTTTTCGGGGTCGGGATCCGGGACAGATTTCACGCTCACAATCTCCTCGCTGGAACCCGAGGACTTCGCGGTCTACTATTGTCATCAGTCATCGATGTTGCCTTTCACGTTTGGACCAG GGACCAAGGTGGACATTAAGiPS: 480711; iPS: 480706; LV-11 GAGATCGTACTTACTCAGTCACCCGCCACATTGTCCCT338 iPS: 480705; iPS: 480707; GAGCCCGGGTGAACGGGCGACCCTCAGCTGCCGAGCAiPS: 480708; iPS: 480712; TCCAAATCCGTCGGGTGGAGCTTGCACTGGTACCAACiPS: 480704; iPS: 480710 AAAAACCGGGCCAGGCCCCCAGACTTCTGATCAAGTATGCGTCACAGAGCTTGTCGGGTATTCCCGCTCGCTTTTCGGGGTCGGGATCCGGGACAGATTTCACGCTCACAATCTCCTCGCTGGAACCCGAGGACTTCGCGGTCTACTATTGTCATCAGTCATCGAGGTTGCCTTTCACGTTTGGACCA GGGACCAAGGTGGACATTAAGCGTAiPS: 480713 LV-12 GAGATCGTACTTACTCAGTCACCCGCCACATTGTCCCT 339GAGCCCGGGTGAACGGGCGACCCTCAGCTGCCGAGCATCCAAATCCGTCGGGTACAGCTTGCACTGGTACCAACAAAAACCGGGCCAGGCCCCCAGACTTCTGATCAAGTATGCGTCACAGAGCTTGTCGGGTATTCCCGCTCGCTTTTCGGGGTCGGGATCCGGGACAGATTTCACGCTCACAATCTCCTCGCTGGAACCCGAGGACTTCGCGGTCTACTATTGTCATCAGTCATCGAGGTTGCCTTTCACGTTTGGACCAG GGACCAAGGTGGACATTAAGCGTAiPS: 480709 LV-13 GAGATCGTACTTACTCAGTCACCCGCCACATTGTCCCT 340GAGCCCGGGTGAACGGGCGACCCTCAGCTGCCGAGCATCCAAAGCCGTCGGGTGGAGCTTGCACTGGTACCAACAAAAACCGGGCCAGGCCCCCAGACTTCTGATCAAGTATGCGTCACAGAGCTTGTCGGGTATTCCCGCTCGCTTTTCGGGGTCGGGATCCGGGACAGATTTCACGCTCACAATCTCCTCGCTGGAACCCGAGGACTTCGCGGTCTACTATTGTCATCAGTCATCGAGGTTGCCTTTCACGTTTGGACCA GGGACCAAGGTGGACATTAAGCGTAiPS: 480716; iPS: 480715 LV-14 GAGATCGTACTTACTCAGTCACCCGCCACATTGTCCCT341 iPS: 480717 GAGCCCGGGTGAACGGGCGACCCTCAGCTGCCGAGCATCCAAATCAGTCGGTCAGTCTTTGCACTGGTACCAACAAAAACCGGGCCAGGCCCCCAGACTTCTGATCAAGTATGCGTCACAGAGCTTGTCGGGTATTCCCGCTCGCTTTTCGGGGTCGGGATCCGGGACAGATTTCACGCTCACAATCTCCTCGCTGGAACCCGAGGACTTCGCGGTCTACTATTGTCATCAGTCATCGCGTTTGCCTTTCACGTTTGGACCAG GGACCAAGGTGGACATTAAGCGTAiPS: 480714 LV-15 GAGATCGTACTTACTCAGTCACCCGCCACATTGTCCCT 342GAGCCCGGGTGAACGGGCGACCCTCAGCTGCCGAGCATCCCGTTCAGTCGGTCTGGCTTTGCACTGGTACCAACAAAAACCGGGCCAGGCCCCCAGACTTCTGATCAAGTATGCGTCACAGAGCTTGTCGGGTATTCCCGCTCGCTTTTCGGGGTCGGGATCCGGGACAGATTTCACGCTCACAATCTCCTCGCTGGAACCCGAGGACTTCGCGGTCTACTATTGTCATCAGTCATCGTTCTTGCCTTTCACGTTTGGACCAG GGACCAAGGTGGACATTAAGCGTA19H8 variants 19H8 LV-16 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGC 343ATCTGTAGGAGACAGAATCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGGTATTTAAATTGGTATCAACAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGATCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAACAGTCTGCAACCTGAAGATTTTGCAACTTACTTCTGTCAACAGAGTTACAGTCCCCCATTCACTTTCGGCCCTG GGACCAAAGTGGATATCAAACGTACiPS: 448202 LV-17 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGC 344ATCTGTAGGAGACAGAATCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGGTATTTAAATTGGTATCAACAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTTCGCTGGTCAGCGTTTGCAAAGTGGGATCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAACAGTCTGCAACCTGAAGATTTTGCAACTTACTTCTGTCAACAGGCTATCGGTATGCCATACACTTTCGGCCCTG GGACCAAAGTGGATATCAAA iPS: 449375LV-18 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGC 345ATCTGTAGGAGACAGAATCACCATCACTTGCCGGGCAAGTCAGTACATTGTTCGTTACTTAAACTGGTATCAACAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTACGCTGCTCATCATTTGCAAAGTGGGATCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAACAGTCTGCAACCTGAAGATTTTGCAACTTACTTCTGTCAACAGGCTATCCAGGAACCATACACTTTCGGCCCTG GGACCAAAGTGGATATCAAA iPS: 448083LV-19 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGC 346ATCTGTAGGAGACAGAATCACCATCACTTGCCGGGCAAGTCAGACTATTGTTCGTTACTTAAACTGGTATCAACAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTTCGCTGGTCAGCGTTTGCAAAGTGGGATCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAACAGTCTGCAACCTGAAGATTTTGCAACTTACTTCTGTCAACAGGCTATCATCAACCCATACACTTTCGGCCCTG GGACCAAAGTGGATATCAAA iPS: 452128LV-20 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGC 347ATCTGTAGGAGACAGAATCACCATCACTTGCCGGGCAAGTCAGTACATTGTTCGTTACTTAAACTGGTATCAACAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTACGCTGCTAACATGTTGCAAAGTGGGATCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAACAGTCTGCAACCTGAAGATTTTGCAACTTACTTCTGTCAACAGGCTATCAACCAGCCATACACTTTCGGCCCTG GGACCAAAGTGGATATCAAA iPS: 448195LV-21 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGC 348ATCTGTAGGAGACAGAATCACCATCACTTGCCGGGCAAGTCAGAAAATTGCTCGTTACTTAGTTTGGTATCAACAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTACGCTGCTAACATGTTGCAAAGTGGGATCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAACAGTCTGCAACCTGAAGATTTTGCAACTTACTTCTGTCAACAGTCTATCCAGCAGCCATACACTTTCGGCCCTG GGACCAAAGTGGATATCAAA iPS: 448466LV-22 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGC 349ATCTGTAGGAGACAGAATCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGGTATTTAAATTGGTATCAACAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTTCGCTGGTCAGCGTTTGCAAAGTGGGATCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAACAGTCTGCAACCTGAAGATTTTGCAACTTACTTCTGTCAACAGGCTATCCAGCAGCCATACACTTTCGGCCCTG GGACCAAAGTGGATATCAAACGTiPS: 448689 LV-23 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGC 350ATCTGTAGGAGACAGAATCACCATCACTTGCCGGGCAAGTCAGTACATTGTTCGTTACTTAAACTGGTATCAACAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTACGCTTCTTACAACTTGCAAAGTGGGATCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAACAGTCTGCAACCTGAAGATTTTGCAACTTACTTCTGTCAACAGGCTATCATGGCTCCATACACTTTCGGCCCTGG GACCAAAGTGGATATCAAA iPS: 449034LV-24 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGC 351ATCTGTAGGAGACAGAATCACCATCACTTGCCGGGCAAGTCAGCCTATTGCTCAGTACTTAAACTGGTATCAACAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTACGCTGGTCGTTACTTGCAAAGTGGGATCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAACAGTCTGCAACCTGAAGATTTTGCAACTTACTTCTGTCAACAGGCTATCCAGAACCCATACACTTTCGGCCCTGG GACCAAAGTGGATATCAAA iPS: 448075LV-25 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGC 352ATCTGTAGGAGACAGAATCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGGTATTTAAATTGGTATCAACAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTTCGCTGGTCAGCGTTTGCAAAGTGGGATCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAACAGTCTGCAACCTGAAGATTTTGCAACTTACTTCTGTCAACAGGCTATCGTTCAGCCATACACTTTCGGCCCTG GGACCAAAGTGGATATCAAA iPS: 448924LV-26 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGC 353ATCTGTAGGAGACAGAATCACCATCACTTGCCGGGCAAGTCAGCCGATTTCTCGTTACTTATCTTGGTATCAACAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTTCGCTGGTCAGCGTTTGCAAAGTGGGATCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAACAGTCTGCAACCTGAAGATTTTGCAACTTACTTCTGTCAACAGGCTATCTCTATCCCATACACTTTCGGCCCTG GGACCAAAGTGGATATCAAAiPS: 448752; 3575 LV-27 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGC 354ATCTGTAGGAGACAGAATCACCATCACTTGCCGGGCAAGTCAGCAGATTGCTCGTTACTTAAACTGGTATCAACAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTACGCTTCTTACAACTTGCAAAGTGGGATCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAACAGTCTGCAACCTGAAGATTTTGCAACTTACTTCTGTCAACAGGCTATCATCCAGCCATACACTTTCGGCCCTGG GACCAAAGTGGATATCAAAiPS: 448772; iPS: 448593 LV-28 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGC355 ATCTGTAGGAGACAGAATCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGGTATTTAAATTGGTATCAACAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTACGCTTCTTACAACTTGCAAAGTGGGATCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAACAGTCTGCAACCTGAAGATTTTGCAACTTACTTCTGTCAACAGGCTATCCAGAACCCATACACTTTCGGCCCTG GGACCAAAGTGGATATCAAA iPS: 448117LV-29 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGC 356ATCTGTAGGAGACAGAATCACCATCACTTGCCGGGCAAGTCAGACTATTGTTCGTTACTTAAACTGGTATCAACAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTTCGCTGGTCAGCGTTTGCAAAGTGGGATCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAACAGTCTGCAACCTGAAGATTTTGCAACTTACTTCTGTCAACAGTCTATCCAGACTCCATACACTTTCGGCCCTG GGACCAAAGTGGATATCAAA iPS: 448788LV-30 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGC 357ATCTGTAGGAGACAGAATCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGGTATTTAAATTGGTATCAACAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTACGCTGGTCGTATCTTGCAAAGTGGGATCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAACAGTCTGCAACCTGAAGATTTTGCAACTTACTTCTGTCAACAGGCTATCATCAACCCATACACTTTCGGCCCTG GGACCAAAGTGGATATCAAA iPS: 448238LV-31 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGC 358ATCTGTAGGAGACAGAATCACCATCACTTGCCGGGCAAGTCAGCGTATTGCTCGTTACTTAAACTGGTATCAACAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTTCGCTGGTTCTATCTTGCAAAGTGGGATCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAACAGTCTGCAACCTGAAGATTTTGCAACTTACTTCTGTCAACAGGCTATCCAGAACCCATACACTTTCGGCCCTGG GACCAAAGTGGATATCAAA iPS: 448901LV-32 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGC 359ATCTGTAGGAGACAGAATCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGGTATTTAAATTGGTATCAACAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTACGCTTCTTACAACTTGCAAAGTGGGATCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAACAGTCTGCAACCTGAAGATTTTGCAACTTACTTCTGTCAACAGTCTATCCAGCAGCCATACACTTTCGGCCCTG GGACCAAAGTGGATATCAAA iPS: 448655LV-33 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGC 360ATCTGTAGGAGACAGAATCACCATCACTTGCCGGGCAAGTCAGTACATTGTTCGTTACTTAAACTGGTATCAACAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTACGCTTCTTACAACTTGCAAAGTGGGATCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAACAGTCTGCAACCTGAAGATTTTGCAACTTACTTCTGTCAACAGGCTATCCAGCAGCCATACACTTTCGGCCCTGG GACCAAAGTGGATATCAAA iPS: 448730LV-34 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGC 361ATCTGTAGGAGACAGAATCACCATCACTTGCCGGGCAAGTCAGATGATTGCTCGTTACTTAAACTGGTATCAACAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTACGCTTCTTACAACTTGCAAAGTGGGATCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAACAGTCTGCAACCTGAAGATTTTGCAACTTACTTCTGTCAACAGGCTATCATCAACCCATACACTTTCGGCCCTGG GACCAAAGTGGATATCAAA iPS: 449027LV-35 GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGC 362ATCTGTAGGAGACAGAATCACCATCACTTGCCGGGCAAGTCAGTACATTGTTCGTTACTTAAACTGGTATCAACAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTACGGTGCTCGTAACTTGCAAAGTGGGATCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAACAGTCTGCAACCTGAAGATTTTGCAACTTACTTCTGTCAACAGTCTATCCAGACTCCATACACTTTCGGCCCTG GGACCAAAGTGGATATCAAA 3574 LV-36GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGC 363ATCTGTAGGAGACAGAATCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGGTATTTAAATTGGTATCAACAGAAACCAGGGAAAGCCCCTAAACTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGATCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAACAGTCTGCAACCTGAAGATTTTGCAACTTACTTCTGTCAACAGAGTTACAGTCCCCCATTCACTTTCGGCCCTG GGACCAAAGTGGATATCAAA

TABLE 5BExemplary Anti-PAC1 Antibody Heavy Chain Variable Region Nucleic AcidSequences VH SEQ ID Ab ID. Group VH Nucleic Acid Sequence NO:29G4 variants 29G4v10; HV-01CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 364 iPS: 421151;GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAG iPS: 391478;TAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCT iPS: 421157;GGAGTGGGTGGCAGTTATATCATATGATGGAGGAAATAAATACT iPS: 421189;ATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATT iPS: 421195;CCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAG iPS: 421201GACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCC TCAGC 29G4v22 HV-02CAAGTTCAGTTGGTGGAGTCTGGAGCCGAAGTAGTAAAGCCAGG 365AGCTTCAGTGAAAGTCTCTTGTAAAGCAAGTGGATTCACGTTTAGCCGCTTTGCCATGCATTGGGTGCGGCAAGCTCCCGGTCAGGGGTTGGAGTGGATGGGAGTTATTAGCTATGACGGGGGCAATAAGTACTACGCCGAGTCTGTTAAGGGTCGGGTCACAATGACACGGGACACCTCAACCAGTACACTCTATATGGAACTGTCTAGCCTGAGATCCGAGGACACCGCTGTGTATTATTGCGCTAGGGGGTACGATGTATTGACGGGTTATCCTGATTACTGGGGGCAGGGGACACTCGTAACCGTCTCTA GT iPS: 420649; HV-03CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 366 iPS: 421227;GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAG iPS: 421231;TAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCT iPS: 421235GGAGTGGGTGGCAGTTATATCATATAACGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420653 HV-04CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 367GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATATCGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420657 HV-05CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 368GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATCAGGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420661 HV-06CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 369GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATTACGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420665; HV-07CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 370 iPS: 421274;GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAG iPS: 421278;TAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCT iPS: 421282GGAGTGGGTGGCAGTTATATCATATGATGGACGCAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420672 HV-08CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 371GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAAACAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420679; HV-09CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 372 iPS: 421314;GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAG iPS: 421318;TAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCT iPS: 421322GGAGTGGGTGGCAGTTATATCATATGATGGAGGAAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420686; HV-10CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 373 iPS: 421361;GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAG iPS: 421365;TAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCT iPS: 421369GGAGTGGGTGGCAGTTATATCATATGATGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420690; HV-11CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 374 iPS: 420837GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATAACGGACGCAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420697; HV-12CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 375 iPS: 420841GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATATCGGACGCAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCTA GT iPS: 420704; HV-13CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 376 iPS: 420845GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATCAGGGACGCAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420711; HV-14CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 377 iPS: 420849GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATTACGGACGCAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCTA GT iPS: 420718; HV-15CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 378 iPS: 420853GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATAACGGAAACAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420725; HV-16CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 379 iPS: 420857GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATATCGGAAACAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420732; HV-17CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 380 iPS: 420861GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATCAGGGAAACAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420739; HV-18CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 381 iPS: 420865GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATTACGGAAACAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420746; HV-19CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 382 iPS: 420869GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATAACGGAGGAAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420753; HV-20CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 383 iPS: 420873GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATATCGGAGGAAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420760; HV-21CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 384 iPS: 420877GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATCAGGGAGGAAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420767; HV-22CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 385 iPS: 420881GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATTACGGAGGAAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420774; HV-23CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 386 iPS: 420885GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATAACGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420781; HV-24CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 387 iPS: 420889GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATATCGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420788; HV-25CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 388 iPS: 420893GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATCAGGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420795; HV-26CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 389 iPS: 420897GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATTACGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420802 HV-27CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 390GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGACGCAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420809 HV-28CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 391GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAAACAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420816 HV-29CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 392GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGACGCAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420823 HV-30CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 393GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAAACAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420830 HV-31CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 394GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAGGAAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420901; HV-32CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 395 iPS: 421027GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATAACGGACGCAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420908; HV-33CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 396 iPS: 421031GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATATCGGACGCAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCTA GT iPS: 420915; HV-34CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 397 iPS: 421035GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATCAGGGACGCAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420922; HV-35CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 398 iPS: 421039GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATTACGGACGCAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCTA GT iPS: 420929; HV-36CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 399 iPS: 421043GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATAACGGAAACAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420936; HV-37CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 400 iPS: 421047GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATATCGGAAACAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420943; HV-38CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 401 iPS: 421051GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATCAGGGAAACAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420950; HV-39CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 402 iPS: 421055GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATTACGGAAACAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420957; HV-40CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 403 iPS: 421059GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATAACGGACGCAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420964; HV-41CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 404 iPS: 421063GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATATCGGACGCAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCTA GT iPS: 420971; HV-42CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 405 iPS: 421067GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATCAGGGACGCAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420978; HV-43CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 406 iPS: 421071GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATTACGGACGCAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCTA GT iPS: 420985; HV-44CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 407 iPS: 421075GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATAACGGAAACAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420992; HV-45CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 408 iPS: 421079GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATATCGGAAACAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 420999; HV-46CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 409 iPS: 421083GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATCAGGGAAACAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421006; HV-47CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 410 iPS: 421087GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATTACGGAAACAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421013 HV-48CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 411GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGACGCAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421020 HV-49CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 412GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAAACAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421091 HV-50CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 413GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATAACGGACGCAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421098 HV-51CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 414GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATATCGGACGCAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCTA GT iPS: 421105 HV-52CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 415GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATCAGGGACGCAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421112 HV-53CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 416GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATTACGGACGCAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCTA GT iPS: 421119 HV-54CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 417GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATAACGGAAACAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421126 HV-55CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 418GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATATCGGAAACAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421133 HV-56CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 419GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATCAGGGAAACAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421140; HV-57CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 420 iPS: 421147GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATTACGGAAACAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421163; HV-58CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 421 iPS: 421207GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTCACTTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 391578; HV-59CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 422 iPS: 421211GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATACGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTC TAGT iPS: 421170; HV-60CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 423 iPS: 421215GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTCGATGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421176; HV-61CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 424 iPS: 421219GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAGCCAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421182; HV-62CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 425 iPS: 421223GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATTTCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421239 HV-63CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 426GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTCACTTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATAACGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421246 HV-64CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 427GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATACGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATAACGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTC TAGT iPS: 421253 HV-65CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 428GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTCAACGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421260 HV-66CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 429GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATAACGGAGCCAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421267 HV-67CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 430GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATAACGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATTTCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421286 HV-68CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 431GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTCACTTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGACGCAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421293 HV-69CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 432GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATACGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGACGCAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421300 HV-70CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 433GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTCGATGGACGCAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCTA GT iPS: 421307 HV-71CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 434GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGACGCAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATTTCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421326 HV-72CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 435GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTCACTTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAGGAAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421333 HV-73CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 436GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATACGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAGGAAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTC TAGT iPS: 421340 HV-74CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 437GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTCGATGGAGGAAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421347 HV-75CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 438GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAGCCAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421354 HV-76CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 439GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAGGAAATAAATACTATGCACGCTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATTTCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421373 HV-77CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 440GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTCACTTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421380 HV-78CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 441GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATACGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTC TAGT iPS: 421387 HV-79CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 442GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTCGATGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421394 HV-80CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 443GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAGCCAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421855 HV-81CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 444GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAAGTACGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTCAAGGGAAGCAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATCTGTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTC TAGT iPS: 421861 HV-82CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 445GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATACGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATCAGGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATCTGTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTC TAGT iPS: 421867 HV-83CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 446GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTCACTTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTCAGCGGAAGCAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATATGTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421873 HV-84CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 447GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAAGTTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATCGCGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATCTGTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421879 HV-85CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 448GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATACGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATAGCGGAGCCAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATCTGTTGAGCGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421885 HV-86CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 449GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTCACTACGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTCAAGGGAGCCAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATCTGTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421891 HV-87CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 450GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTCACTACGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATCGCGGAGCCAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATCTGTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 421897 HV-88CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 451GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTCACTACGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTCTACGGAAGCAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATTTCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCTA GT iPS: 421903 HV-89CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 452GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTCACTTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTCTTCGGAGGAAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATTTCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCTA GT iPS: 421909 HV-90CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 453GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTCACTACGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATTCATGGGAACCAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATTTCTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCTA GT iPS: 421915 HV-91CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 454GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTTACTTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCACACCGCGGAACCAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATCTGTTGAGCGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCT AGT iPS: 480711 HV-92CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 455GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGGTGTTATCAACTATCGTGGACATGGTAAATACTA TGCAGAGTCCGTGAAGGGCCGGTTCACCGTGTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTCTAGT iPS: 480706 HV-93CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 456GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGGTGTTATATCTTTTTCTGGAGGTTCTAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCTTGTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTCTA GT iPS: 480713 HV-94CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 457GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGGTGTTATCTCTTATACTGGACAGTTCAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCGTGTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTCTA GT iPS: 480705 HV-95CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 458GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGGTGTTATATCTTATACTGGAGCTCAGAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATGTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTCTA GT iPS: 480707 HV-96CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 459GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGGTGTTATATCTTATTCTGGAGCTTCTAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATGTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTCTA GT iPS: 480708 HV-97CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 460GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCTGTTATATCTTATTCTGGAGCTTTCAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCGTGTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTCTA GT iPS: 480709 HV-98CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 461GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGGTGTTATAACTTATACTGGAGGTGCTAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTCTA GT iPS: 480712 HV-99CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 462GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGGTGTTATCAACTTTCAGGGAACTACTAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTCTA GT iPS: 480704 HV-100CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 463GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGGTGTTATATCTTATTCTGGAGATCTGAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCGTGTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTCTA GT iPS: 480710 HV-101CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 464GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGATTTGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGGTGTTATCAACTATTTCGGAGACGCTAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATGTTTTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTCTA GT iPS: 480716 HV-102CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 465GAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTTTCTACGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATCTCATCTTTCGGAAGTAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATCTGCTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTCTA GT iPS: 480715 HV-103CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 466GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTTACTACGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATCTCATACTCTGGAAGTAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATCTGCTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTCTA GT iPS: 480717 HV-104CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 467GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTTACTACGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATCTCACATTACGGAACTAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATCCTCTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTCTA GT iPS: 480714 HV-105CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGG 468GAGGTCCCTGCGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTCATTACGCCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATCTCATACCAGGGAAGTAATAAATACTATGCAGAGTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTCTGTTTTACTGTGCGAGAGGATACGATCTGCTGACTGGTTACCCCGACTACTGGGGCCAGGGAACCCTGGTCACCGTGTCT AGT 19H8 variants19H8; 3575 HV-106 CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTC 469GCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGCTACTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATATTACAGGTCCAAGTGGTCTAATCATTATGCAGTATCTGTGAAAAGTCGAATAACCATCAACCCCGACACGTCCAAGAGCCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGGAACGTGGAAACAGCTATGGTTCCTTGACCACTGGGGCCAGGGAACCCTGGTC ACCGTCTCTAGTG iPS: 448202;HV-107 CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTC 470 iPS: 448689GCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAACCGTCTGGCTACTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATACTACAGGGGTAAATGGAAAAATCATTATGCAGTATCTGTGAAAAGTCGAATAACCATCAACCCCGACACGTCCAAGAGCCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGGAACTTGGAACCAGGACTGGTTCCTGGACCACTGGGGCCAGGGAACCCTGGTC ACCGTCTCTAGT iPS: 449375HV-108 CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTC 471GCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAACCGTCTGGCTACTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATACTACAGGGGTAAATGGAAAAATCATTATGCAGTATCTGTGAAAAGTCGAATAACCATCAACCCCGACACGTCCAAGAGCCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGGAACTTGGGACCAGGACTGGTTCCTGGACCACTGGGGCCAGGGAACCCTGGTC ACCGTCTCTAGT iPS: 448083HV-109 CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTC 472GCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTTCTCGTCAGGCTACTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATACTACAGGGGTAAATGGAAAAATCATTATGCAGTATCTGTGAAAAGTCGAATAACCATCAACCCCGACACGTCCAAGAGCCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGGAACTTGGGAACAGGACTGGTTCCTGGACCACTGGGGCCAGGGAACCCTGGTC ACCGTCTCTAGT iPS: 452128;HV-110 CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTC 473 iPS: 448195;GCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTC iPS: 448752;TAACAAACAGGCTACTTGGAACTGGATCAGGCAGTCCCCATCGA iPS: 449027;GAGGCCTTGAGTGGCTGGGAAGGACATACTACAGGGGTAAATGG 3574AAAAATCATTATGCAGTATCTGTGAAAAGTCGAATAACCATCAACCCCGACACGTCCAAGAGCCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGGAATGTGGAACCAGAACTGGTTCCTGGACCACTGGGGCCAGGGAACCCTGG TCACCGTCTCTAGT iPS: 448466HV-111 CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTC 474GCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAACAAACAGGCTACTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATACTACAGGGGTCAGTGGAAAAATCATTATGCAGTATCTGTGAAAAGTCGAATAACCATCAACCCCGACACGTCCAAGAGCCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGGAACTTGGATCGGTGACTGGTTCATGGACCACTGGGGCCAGGGAACCCTGGTC ACCGTCTCTAGT iPS: 449034HV-112 CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTC 475GCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAACAAACAGGCTACTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATACTACAGGGGTAAATGGAAAAATCATTATGCAGTATCTGTGAAAAGTCGAATAACCATCAACCCCGACACGTCCAAGAGCCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGGAACTTGGATCCAGGACTGGTTCCTGGACCACTGGGGCCAGGGAACCCTGGTC ACCGTCTCTAGT iPS: 448075HV-113 CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTC 476GCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTTCTAACCATGCTACTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATACTACAGGGGTAAATGGAAAAATCATTATGCAGTATCTGTGAAAAGTCGAATAACCATCAACCCCGACACGTCCAAGAGCCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGGAACTTGGGACCAGGACTGGTTCCTGGACCACTGGGGCCAGGGAACCCTGGTC ACCGTCTCTAGT iPS: 448924HV-114 CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTC 477GCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTTCTCGTTACGCTACTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATACTACAGGGGTCAGTGGAAAAATCATTATGCAGTATCTGTGAAAAGTCGAATAACCATCAACCCCGACACGTCCAAGAGCCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGGAATGTGGAACCAGAACTGGTTCCTGGACCACTGGGGCCAGGGAACCCTGGT CACCGTCTCTAGT iPS: 448772HV-115 CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTC 478GCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAACAAACAGGCTACTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATACTACAGGGGTAAATGGAAAAATCATTATGCAGTATCTGTGAAAAGTCGAATAACCATCAACCCCGACACGTCCAAGAGCCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGGAATGTGGTCTGGTGACTGGTTCCTGGACCACTGGGGCCAGGGAACCCTGGT CACCGTCTCTAGT iPS: 448117HV-116 CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTC 479GCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTTCTCATGTTGCTACTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATACTACAGGGGTAAATGGAAAAATCATTATGCAGTATCTGTGAAAAGTCGAATAACCATCAACCCCGACACGTCCAAGAGCCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGGAATGTGGTCTGAAGACTGGTTCCTGGACCACTGGGGCCAGGGAACCCTGGTC ACCGTCTCTAGT iPS: 448788HV-117 CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTC 480GCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTTCTCGTCAGGCTACTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATACTACAGGGGTAAATGGAAAAATCATTATGCAGTATCTGTGAAAAGTCGAATAACCATCAACCCCGACACGTCCAAGAGCCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGGAATGTGGCAGGGTAACTGGTTCCTGGACCACTGGGGCCAGGGAACCCTGGTC ACCGTCTCTAGT iPS: 448593HV-118 CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTC 481GCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAACCATCAGGCTACTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATACTACAGGGGTAAATGGAAAAATCATTATGCAGTATCTGTGAAAAGTCGAATAACCATCAACCCCGACACGTCCAAGAGCCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGGAACTTGGATCCAGGACTGGTTCCTGGACCACTGGGGCCAGGGAACCCTGGTCA CCGTCTCTAGT iPS: 448238HV-119 CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTC 482GCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTTCTCGTGACGCTACTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATACTACAGGGGTAAATGGAAAAATCATTATGCAGTATCTGTGAAAAGTCGAATAACCATCAACCCCGACACGTCCAAGAGCCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGGACAGTGGAACGAAGACTGGTTCCTGGACCACTGGGGCCAGGGAACCCTGGT CACCGTCTCTAGT iPS: 448901HV-120 CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTC 483GCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAACCGTCTGGCTACTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATACTACAGGGGTAAATGGAAAAATCATTATGCAGTATCTGTGAAAAGTCGAATAACCATCAACCCCGACACGTCCAAGAGCCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGGACGTTGGGAAGGTGACTGGTTCTTCGACCACTGGGGCCAGGGAACCCTGGTCA CCGTCTCTAGT iPS: 448655HV-121 CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTC 484GCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAACAAACAGGCTACTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATACTTCAGGCGTACTTGGAAAAATCATTATGCAGTATCTGTGAAAAGTCGAATAACCATCAACCCCGACACGTCCAAGAGCCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGGAATGTGGTCTGAAGACTGGTTCCTGGACCACTGGGGCCAGGGAACCCTGGT CACCGTCTCTAGT iPS: 448730HV-122 CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTC 485GCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAACCGTCTGGCTACTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATACTACAGGGGTAAATGGAAAAATCATTATGCAGTATCTGTGAAAAGTCGAATAACCATCAACCCCGACACGTCCAAGAGCCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGGAGTTTGGATCGGTAACTGGTTCCTGGACCACTGGGGCCAGGGAACCCTGGTCA CCGTCTCTAGT

Isolated nucleic acids encoding the anti-PAC1 antibodies orantigen-binding fragments of the invention may comprise a nucleotidesequence that is at least 80% identical, at least 90% identical, atleast 95% identical, or at least 98% identical to any of the nucleotidesequences listed in Tables 4A, 4B, 5A, and 5B. In some embodiments, anisolated nucleic acid encoding an anti-PAC1 antibody light chainvariable region comprises a sequence that is at least 80% identical, atleast 90% identical, at least 95% identical, or at least 98% identicalto a sequence selected from SEQ ID NOs: 328 to 342. In otherembodiments, an isolated nucleic acid encoding an anti-PAC1 antibodylight chain variable region comprises a sequence that is at least 80%identical, at least 90% identical, at least 95% identical, or at least98% identical to a sequence selected from SEQ ID NOs: 343 to 363. Incertain embodiments, an isolated nucleic acid encoding an anti-PAC1antibody light chain variable region comprises a sequence selected fromSEQ ID NOs: 328 to 342. In certain other embodiments, an isolatednucleic acid encoding an anti-PAC1 antibody light chain variable regioncomprises a sequence selected from SEQ ID NOs: 343 to 363. In relatedembodiments, an isolated nucleic acid encoding an anti-PAC1 antibodyheavy chain variable region comprises a sequence that is at least 80%identical, at least 90% identical, at least 95% identical, or at least98% identical to a sequence selected from SEQ ID NOs: 364 to 468. Inother related embodiments, an isolated nucleic acid encoding ananti-PAC1 antibody heavy chain variable region comprises a sequence thatis at least 80% identical, at least 90% identical, at least 95%identical, or at least 98% identical to a sequence selected from SEQ IDNOs: 469 to 485. In some embodiments, an isolated nucleic acid encodingan anti-PAC1 antibody heavy chain variable region comprises a sequenceselected from SEQ ID NOs: 364 to 468. In other embodiments, an isolatednucleic acid encoding an anti-PAC1 antibody heavy chain variable regioncomprises a sequence selected from SEQ ID NOs: 469 to 485.

In some embodiments, an isolated nucleic acid encoding an anti-PAC1antibody light chain comprises a sequence that is at least 80%identical, at least 90% identical, at least 95% identical, or at least98% identical to a sequence selected from SEQ ID NOs: 537 to 541. Inother embodiments, an isolated nucleic acid encoding an anti-PAC1antibody light chain comprises a sequence that is at least 80%identical, at least 90% identical, at least 95% identical, or at least98% identical to a sequence selected from SEQ ID NOs: 542 to 551. Incertain embodiments, an isolated nucleic acid encoding an anti-PAC1antibody light chain comprises a sequence selected from SEQ ID NOs: 537to 541. In certain other embodiments, an isolated nucleic acid encodingan anti-PAC1 antibody light chain comprises a sequence selected from SEQID NOs: 542 to 551. In related embodiments, an isolated nucleic acidencoding an anti-PAC1 antibody heavy chain comprises a sequence that isat least 80% identical, at least 90% identical, at least 95% identical,or at least 98% identical to a sequence selected from SEQ ID NOs: 552 to562. In other related embodiments, an isolated nucleic acid encoding ananti-PAC1 antibody heavy chain comprises a sequence that is at least 80%identical, at least 90% identical, at least 95% identical, or at least98% identical to a sequence selected from SEQ ID NOs: 563 to 569. Insome embodiments, an isolated nucleic acid encoding an anti-PAC1antibody heavy chain comprises a sequence selected from SEQ ID NOs: 552to 562. In other embodiments, an isolated nucleic acid encoding ananti-PAC1 antibody heavy chain comprises a sequence selected from SEQ IDNOs: 563 to 569.

The nucleic acid sequences provided in Tables 4A, 4B, 5A, and 5B areexemplary only. As will be appreciated by those in the art, due to thedegeneracy of the genetic code, an extremely large number of nucleicacids may be made, all of which encode the CDRs, variable regions, andheavy and light chains or other components of the antibodies andantigen-binding fragments described herein. Thus, having identified aparticular amino acid sequence, those skilled in the art could make anynumber of different nucleic acids, by simply modifying the sequence ofone or more codons in a way which does not change the amino acidsequence of the encoded protein.

The present invention also includes vectors comprising one or morenucleic acids encoding one or more components of the antibodies orantigen-binding fragments of the invention (e.g. variable regions, lightchains, and heavy chains). The term “vector” refers to any molecule orentity (e.g., nucleic acid, plasmid, bacteriophage or virus) used totransfer protein coding information into a host cell. Examples ofvectors include, but are not limited to, plasmids, viral vectors,non-episomal mammalian vectors and expression vectors, for example,recombinant expression vectors. The term “expression vector” or“expression construct” as used herein refers to a recombinant DNAmolecule containing a desired coding sequence and appropriate nucleicacid control sequences necessary for the expression of the operablylinked coding sequence in a particular host cell. An expression vectorcan include, but is not limited to, sequences that affect or controltranscription, translation, and, if introns are present, affect RNAsplicing of a coding region operably linked thereto. Nucleic acidsequences necessary for expression in prokaryotes include a promoter,optionally an operator sequence, a ribosome binding site and possiblyother sequences. Eukaryotic cells are known to utilize promoters,enhancers, and termination and polyadenylation signals.

A secretory signal peptide sequence can also, optionally, be encoded bythe expression vector, operably linked to the coding sequence ofinterest, so that the expressed polypeptide can be secreted by therecombinant host cell, for more facile isolation of the polypeptide ofinterest from the cell, if desired. For instance, in some embodiments,signal peptide sequences may be appended/fused to the amino terminus ofany of the variable region polypeptide sequences listed in Tables 1A and1B or any of the full chain polypeptide sequences listed in Tables 4Aand 4B. In certain embodiments, a signal peptide having the amino acidsequence of MDMRVPAQLLGLLLLWLRGARC (SEQ ID NO: 486) is fused to theamino terminus of any of the variable region polypeptide sequences inTables 1A and 1B or full chain polypeptide sequences in Tables 4A and4B. In other embodiments, a signal peptide having the amino acidsequence of MAWALLLLTLLTQGTGSWA (SEQ ID NO: 487) is fused to the aminoterminus of any of the variable region polypeptide sequences in Tables1A and 1B or full chain polypeptide sequences in Tables 4A and 4B. Instill other embodiments, a signal peptide having the amino acid sequenceof MTCSPLLLTLLIHCTGSWA (SEQ ID NO: 488) is fused to the amino terminusof any of the variable region polypeptide sequences in Tables 1A and 1Bor full chain polypeptide sequences in Tables 4A and 4B. Other suitablesignal peptide sequences that can be fused to the amino terminus of thevariable region polypeptide sequences or full chain polypeptidesequences described herein include: MEAPAQLLFLLLLWLPDTTG (SEQ ID NO:489), MEWTWRVLFLVAAATGAHS (SEQ ID NO: 490), METPAQLLFLLLLWLPDTTG (SEQ IDNO: 491), METPAQLLFLLLLWLPDTTG (SEQ ID NO: 492), MKHLWFFLLLVAAPRWVLS(SEQ ID NO: 493), MEWSWVFLFFLSVTTGVHS (SEQ ID NO: 494),MDIRAPTQLLGLLLLWLPGAKC (SEQ ID NO: 495), MDIRAPTQLLGLLLLWLPGARC (SEQ IDNO: 496), MDTRAPTQLLGLLLLWLPGATF (SEQ ID NO: 497),MDTRAPTQLLGLLLLWLPGARC (SEQ ID NO: 498), METGLRWLLLVAVLKGVQC (SEQ ID NO:499), METGLRWLLLVAVLKGVQCQE (SEQ ID NO: 500), and MDMRAPTQLLGLLLLWLPGARC(SEQ ID NO: 501). Other signal or secretory peptides are known to thoseof skill in the art and may be fused to any of the variable regionpolypeptide chains listed in Tables 1A and 1B or full chain polypeptidesequences in Tables 4A and 4B, for example, to facilitate or optimizeexpression in particular host cells.

Typically, expression vectors used in the host cells to produce theanti-PAC1 antibodies and antigen-binding fragments of the invention willcontain sequences for plasmid maintenance and for cloning and expressionof exogenous nucleotide sequences encoding the components of theantibodies and antigen-binding fragments. Such sequences, collectivelyreferred to as “flanking sequences,” in certain embodiments willtypically include one or more of the following nucleotide sequences: apromoter, one or more enhancer sequences, an origin of replication, atranscriptional termination sequence, a complete intron sequencecontaining a donor and acceptor splice site, a sequence encoding aleader sequence for polypeptide secretion, a ribosome binding site, apolyadenylation sequence, a polylinker region for inserting the nucleicacid encoding the polypeptide to be expressed, and a selectable markerelement. Each of these sequences is discussed below.

Optionally, the vector may contain a “tag”-encoding sequence, i.e., anoligonucleotide molecule located at the 5′ or 3′ end of the polypeptidecoding sequence; the oligonucleotide tag sequence encodes polyHis (suchas hexaHis), FLAG, HA (hemaglutinin influenza virus), myc, or another“tag” molecule for which commercially available antibodies exist. Thistag is typically fused to the polypeptide upon expression of thepolypeptide, and can serve as a means for affinity purification ordetection of the polypeptide from the host cell. Affinity purificationcan be accomplished, for example, by column chromatography usingantibodies against the tag as an affinity matrix. Optionally, the tagcan subsequently be removed from the purified polypeptide by variousmeans such as using certain peptidases for cleavage.

Flanking sequences may be homologous (i.e., from the same species and/orstrain as the host cell), heterologous (i.e., from a species other thanthe host cell species or strain), hybrid (i.e., a combination offlanking sequences from more than one source), synthetic or native. Assuch, the source of a flanking sequence may be any prokaryotic oreukaryotic organism, any vertebrate or invertebrate organism, or anyplant, provided that the flanking sequence is functional in, and can beactivated by, the host cell machinery.

Flanking sequences useful in the vectors of this invention may beobtained by any of several methods well known in the art. Typically,flanking sequences useful herein will have been previously identified bymapping and/or by restriction endonuclease digestion and can thus beisolated from the proper tissue source using the appropriate restrictionendonucleases. In some cases, the full nucleotide sequence of a flankingsequence may be known. Here, the flanking sequence may be synthesizedusing routine methods for nucleic acid synthesis or cloning.

Whether all or only a portion of the flanking sequence is known, it maybe obtained using polymerase chain reaction (PCR) and/or by screening agenomic library with a suitable probe such as an oligonucleotide and/orflanking sequence fragment from the same or another species. Where theflanking sequence is not known, a fragment of DNA containing a flankingsequence may be isolated from a larger piece of DNA that may contain,for example, a coding sequence or even another gene or genes. Isolationmay be accomplished by restriction endonuclease digestion to produce theproper DNA fragment followed by isolation using agarose gelpurification, Qiagen® column chromatography (Chatsworth, Calif.), orother methods known to the skilled artisan. The selection of suitableenzymes to accomplish this purpose will be readily apparent to one ofordinary skill in the art.

An origin of replication is typically a part of those prokaryoticexpression vectors purchased commercially, and the origin aids in theamplification of the vector in a host cell. If the vector of choice doesnot contain an origin of replication site, one may be chemicallysynthesized based on a known sequence, and ligated into the vector. Forexample, the origin of replication from the plasmid pBR322 (New EnglandBiolabs, Beverly, Mass.) is suitable for most gram-negative bacteria,and various viral origins (e.g., SV40, polyoma, adenovirus, vesicularstomatitus virus (VSV), or papillomaviruses such as HPV or BPV) areuseful for cloning vectors in mammalian cells. Generally, the origin ofreplication component is not needed for mammalian expression vectors(for example, the SV40 origin is often used only because it alsocontains the virus early promoter).

A transcription termination sequence is typically located 3′ to the endof a polypeptide coding region and serves to terminate transcription.Usually, a transcription termination sequence in prokaryotic cells is aG-C rich fragment followed by a poly-T sequence. While the sequence iseasily cloned from a library or even purchased commercially as part of avector, it can also be readily synthesized using known methods fornucleic acid synthesis.

A selectable marker gene encodes a protein necessary for the survivaland growth of a host cell grown in a selective culture medium. Typicalselection marker genes encode proteins that (a) confer resistance toantibiotics or other toxins, e.g., ampicillin, tetracycline, orkanamycin for prokaryotic host cells; (b) complement auxotrophicdeficiencies of the cell; or (c) supply critical nutrients not availablefrom complex or defined media. Specific selectable markers are thekanamycin resistance gene, the ampicillin resistance gene, and thetetracycline resistance gene. Advantageously, a neomycin resistance genemay also be used for selection in both prokaryotic and eukaryotic hostcells.

Other selectable genes may be used to amplify the gene that will beexpressed.

Amplification is the process wherein genes that are required forproduction of a protein critical for growth or cell survival arereiterated in tandem within the chromosomes of successive generations ofrecombinant cells. Examples of suitable selectable markers for mammaliancells include dihydrofolate reductase (DHFR) and promoterless thymidinekinase genes. Mammalian cell transformants are placed under selectionpressure wherein only the transformants are uniquely adapted to surviveby virtue of the selectable gene present in the vector. Selectionpressure is imposed by culturing the transformed cells under conditionsin which the concentration of selection agent in the medium issuccessively increased, thereby leading to the amplification of both theselectable gene and the DNA that encodes another gene, such as one ormore components of the antibodies or antigen-binding fragments describedherein. As a result, increased quantities of a polypeptide aresynthesized from the amplified DNA.

A ribosome-binding site is usually necessary for translation initiationof mRNA and is characterized by a Shine-Dalgarno sequence (prokaryotes)or a Kozak sequence (eukaryotes). The element is typically located 3′ tothe promoter and 5′ to the coding sequence of the polypeptide to beexpressed. In certain embodiments, one or more coding regions may beoperably linked to an internal ribosome binding site (IRES), allowingtranslation of two open reading frames from a single RNA transcript.

In some cases, such as where glycosylation is desired in a eukaryotichost cell expression system, one may manipulate the various pre- orprosequences to improve glycosylation or yield. For example, one mayalter the peptidase cleavage site of a particular signal peptide, or addprosequences, which also may affect glycosylation. The final proteinproduct may have, in the −1 position (relative to the first amino acidof the mature protein) one or more additional amino acids incident toexpression, which may not have been totally removed. For example, thefinal protein product may have one or two amino acid residues found inthe peptidase cleavage site, attached to the amino-terminus.Alternatively, use of some enzyme cleavage sites may result in aslightly truncated form of the desired polypeptide, if the enzyme cutsat such area within the mature polypeptide.

Expression and cloning vectors of the invention will typically contain apromoter that is recognized by the host organism and operably linked tothe molecule encoding the polypeptide. The term “operably linked” asused herein refers to the linkage of two or more nucleic acid sequencesin such a manner that a nucleic acid molecule capable of directing thetranscription of a given gene and/or the synthesis of a desired proteinmolecule is produced. For example, a control sequence in a vector thatis “operably linked” to a protein coding sequence is ligated thereto sothat expression of the protein coding sequence is achieved underconditions compatible with the transcriptional activity of the controlsequences. More specifically, a promoter and/or enhancer sequence,including any combination of cis-acting transcriptional control elementsis operably linked to a coding sequence if it stimulates or modulatesthe transcription of the coding sequence in an appropriate host cell orother expression system.

Promoters are non-transcribed sequences located upstream (i.e., 5′) tothe start codon of a structural gene (generally within about 100 to 1000bp) that control transcription of the structural gene. Promoters areconventionally grouped into one of two classes: inducible promoters andconstitutive promoters. Inducible promoters initiate increased levels oftranscription from DNA under their control in response to some change inculture conditions, such as the presence or absence of a nutrient or achange in temperature. Constitutive promoters, on the other hand,uniformly transcribe a gene to which they are operably linked, that is,with little or no control over gene expression. A large number ofpromoters, recognized by a variety of potential host cells, are wellknown. A suitable promoter is operably linked to the DNA encoding e.g.,heavy chain, light chain, or other component of the antibodies andantigen-binding fragments of the invention, by removing the promoterfrom the source DNA by restriction enzyme digestion and inserting thedesired promoter sequence into the vector.

Suitable promoters for use with yeast hosts are also well known in theart. Yeast enhancers are advantageously used with yeast promoters.Suitable promoters for use with mammalian host cells are well known andinclude, but are not limited to, those obtained from the genomes ofviruses such as polyoma virus, fowlpox virus, adenovirus (such asAdenovirus serotypes 2, 8, or 9), bovine papilloma virus, avian sarcomavirus, cytomegalovirus, retroviruses, hepatitis-B virus and Simian Virus40 (SV40). Other suitable mammalian promoters include heterologousmammalian promoters, for example, heat-shock promoters and the actinpromoter.

Additional specific promoters which may be of interest include, but arenot limited to: SV40 early promoter (Benoist and Chambon, 1981, Nature290:304-310); CMV promoter (Thornsen et al., 1984, Proc. Natl. Acad.U.S.A. 81:659-663); the promoter contained in the 3′ long terminalrepeat of Rous sarcoma virus (Yamamoto et al., 1980, Cell 22:787-797);herpes thymidine kinase promoter (Wagner et al., 1981, Proc. Natl. Acad.Sci. U.S.A. 78: 1444-1445); promoter and regulatory sequences from themetallothionine gene (Prinster et al., 1982, Nature 296:39-42); andprokaryotic promoters such as the beta-lactamase promoter(Villa-Kamaroff et al., 1978, Proc. Natl. Acad. Sci. U.S.A.75:3727-3731); or the tac promoter (DeBoer et al., 1983, Proc. Natl.Acad. Sci. U.S.A. 80:21-25). Also of interest are the following animaltranscriptional control regions, which exhibit tissue specificity andhave been utilized in transgenic animals: the elastase I gene controlregion that is active in pancreatic acinar cells (Swift et al., 1984,Cell 38:639-646; Ornitz et al., 1986, Cold Spring Harbor Symp. Quant.Biol. 50:399-409; MacDonald, 1987, Hepatology 7:425-515); the insulingene control region that is active in pancreatic beta cells (Hanahan,1985, Nature 315: 115-122); the immunoglobulin gene control region thatis active in lymphoid cells (Grosschedl et al., 1984, Cell 38:647-658;Adames et al., 1985, Nature 318:533-538; Alexander et al., 1987, Mol.Cell. Biol. 7: 1436-1444); the mouse mammary tumor virus control regionthat is active in testicular, breast, lymphoid and mast cells (Leder etal., 1986, Cell 45:485-495); the albumin gene control region that isactive in liver (Pinkert et al., 1987, Genes and Devel. 1:268-276); thealpha-feto-protein gene control region that is active in liver (Krumlaufet al., 1985, Mol. Cell. Biol. 5: 1639-1648; Hammer et al., 1987,Science 253:53-58); the alpha 1-antitrypsin gene control region that isactive in liver (Kelsey et al., 1987, Genes and Devel. 1: 161-171); thebeta-globin gene control region that is active in myeloid cells (Mogramet al, 1985, Nature 315:338-340; Kollias et al, 1986, Cell 46:89-94);the myelin basic protein gene control region that is active inoligodendrocyte cells in the brain (Readhead et al., 1987, Cell48:703-712); the myosin light chain-2 gene control region that is activein skeletal muscle (Sani, 1985, Nature 314:283-286); and thegonadotropic releasing hormone gene control region that is active in thehypothalamus (Mason et al., 1986, Science 234: 1372-1378).

An enhancer sequence may be inserted into the vector to increasetranscription of DNA encoding a component of the antibodies orantigen-binding fragments (e.g., light chain, heavy chain, or variableregions) by higher eukaryotes. Enhancers are cis-acting elements of DNA,usually about 10-300 bp in length, that act on the promoter to increasetranscription. Enhancers are relatively orientation and positionindependent, having been found at positions both 5′ and 3′ to thetranscription unit. Several enhancer sequences available from mammaliangenes are known (e.g., globin, elastase, albumin, alpha-feto-protein andinsulin). Typically, however, an enhancer from a virus is used. The SV40enhancer, the cytomegalovirus early promoter enhancer, the polyomaenhancer, and adenovirus enhancers known in the art are exemplaryenhancing elements for the activation of eukaryotic promoters. While anenhancer may be positioned in the vector either 5′ or 3′ to a codingsequence, it is typically located at a site 5′ from the promoter. Asequence encoding an appropriate native or heterologous signal sequence(leader sequence or signal peptide) can be incorporated into anexpression vector, to promote extracellular secretion of the antibody orantigen-binding fragment as described above. The choice of signalpeptide or leader depends on the type of host cells in which theantibody or antigen-binding fragment is to be produced, and aheterologous signal sequence can replace the native signal sequence.Examples of signal peptides are described above. Other signal peptidesthat are functional in mammalian host cells include the signal sequencefor interleukin-7 (IL-7) described in U.S. Pat. No. 4,965,195; thesignal sequence for interleukin-2 receptor described in Cosman et al.,1984, Nature 312:768; the interleukin-4 receptor signal peptidedescribed in EP Patent No. 0367 566; the type I interleukin-1 receptorsignal peptide described in U.S. Pat. No. 4,968,607; and the type IIinterleukin-1 receptor signal peptide described in EP Patent No. 0 460846.

The expression vectors that are provided may be constructed from astarting vector such as a commercially available vector. Such vectorsmay or may not contain all of the desired flanking sequences. Where oneor more of the flanking sequences described herein are not alreadypresent in the vector, they may be individually obtained and ligatedinto the vector. Methods used for obtaining each of the flankingsequences are well known to one skilled in the art. The expressionvectors can be introduced into host cells to thereby produce proteins,including antibodies and antigen-binding fragments, encoded by nucleicacids as described herein.

In certain embodiments, nucleic acids encoding the different componentsof the anti-PAC1 antibodies or antigen-binding fragments of theinvention may be inserted into the same expression vector. For instance,the nucleic acid encoding an anti-PAC1 antibody light chain or variableregion can be cloned into the same vector as the nucleic acid encodingan anti-PAC1 antibody heavy chain or variable region. In suchembodiments, the two nucleic acids may be separated by an internalribosome entry site (IRES) and under the control of a single promotersuch that the light chain and heavy chain are expressed from the samemRNA transcript. Alternatively, the two nucleic acids may be under thecontrol of two separate promoters such that the light chain and heavychain are expressed from two separate mRNA transcripts. In someembodiments, the nucleic acid encoding the anti-PAC1 antibody lightchain or variable region is cloned into one expression vector and thenucleic acid encoding the anti-PAC1 antibody heavy chain or variableregion is cloned into a second expression vector. In such embodiments, ahost cell may be co-transfected with both expression vectors to producecomplete antibodies or antigen-binding fragments of the invention.

After the vector has been constructed and the one or more nucleic acidmolecules encoding the components of the antibodies and antigen-bindingfragments described herein has been inserted into the proper site(s) ofthe vector or vectors, the completed vector(s) may be inserted into asuitable host cell for amplification and/or polypeptide expression.Thus, the present invention encompasses an isolated host cell or cellline comprising one or more expression vectors encoding the componentsof the anti-PAC1 antibodies or antigen-binding fragments describedherein. The term “host cell” as used herein refers to a cell that hasbeen transformed, or is capable of being transformed, with a nucleicacid and thereby expresses a gene of interest. The term includes theprogeny of the parent cell, whether or not the progeny is identical inmorphology or in genetic make-up to the original parent cell, so long asthe gene of interest is present. A host cell that comprises an isolatednucleic acid of the invention, preferably operably linked to at leastone expression control sequence (e.g. promoter or enhancer), is a“recombinant host cell.”

The transformation of an expression vector for an anti-PAC1 antibody orantigen-binding fragment into a selected host cell may be accomplishedby well-known methods including transfection, infection, calciumphosphate co-precipitation, electroporation, microinjection,lipofection, DEAE-dextran mediated transfection, or other knowntechniques. The method selected will in part be a function of the typeof host cell to be used. These methods and other suitable methods arewell known to the skilled artisan, and are set forth, for example, inSambrook et al., 2001.

A host cell, when cultured under appropriate conditions, synthesizes anantibody or antigen-binding fragment that can subsequently be collectedfrom the culture medium (if the host cell secretes it into the medium)or directly from the host cell producing it (if it is not secreted). Theselection of an appropriate host cell will depend upon various factors,such as desired expression levels, polypeptide modifications that aredesirable or necessary for activity (such as glycosylation orphosphorylation) and ease of folding into a biologically activemolecule.

Exemplary host cells include prokaryote, yeast, or higher eukaryotecells. Prokaryotic host cells include eubacteria, such as Gram-negativeor Gram-positive organisms, for example, Enterobacteriaceae such asEscherichia, e.g., E. coli, Enterobacter, Erwinia, Klebsiella, Proteus,Salmonella, e.g., Salmonella typhimurium, Serratia, e.g., Serratiamarcescans, and Shigella, as well as Bacillus, such as B. subtilis andB. licheniformis, Pseudomonas, and Streptomyces. Eukaryotic microbessuch as filamentous fungi or yeast are suitable cloning or expressionhosts for recombinant polypeptides. Saccharomyces cerevisiae, or commonbaker's yeast, is the most commonly used among lower eukaryotic hostmicroorganisms. However, a number of other genera, species, and strainsare commonly available and useful herein, such as Pichia, e.g. P.pastoris, Schizosaccharomyces pombe; Kluyveromyces, Yarrowia; Candida;Trichoderma reesia; Neurospora crassa; Schwanniomyces, such asSchwanniomyces occidentalis; and filamentous fungi, such as, e.g.,Neurospora, Penicillium, Tolypocladium, and Aspergillus hosts such as A.nidulans and A. niger.

Host cells for the expression of glycosylated antibodies andantigen-binding fragments can be derived from multicellular organisms.Examples of invertebrate cells include plant and insect cells. Numerousbaculoviral strains and variants and corresponding permissive insecthost cells from hosts such as Spodoptera frugiperda (caterpillar), Aedesaegypti (mosquito), Aedes albopictus (mosquito), Drosophila melanogaster(fruitfly), and Bombyx mori have been identified. A variety of viralstrains for transfection of such cells are publicly available, e.g., theL-1 variant of Autographa californica NPV and the Bm-5 strain of Bombyxmori NPV.

Vertebrate host cells are also suitable hosts, and recombinantproduction of antibodies and antigen-binding fragments from such cellshas become routine procedure. Mammalian cell lines available as hostsfor expression are well known in the art and include, but are notlimited to, immortalized cell lines available from the American TypeCulture Collection (ATCC), including but not limited to Chinese hamsterovary (CHO) cells, including CHOK1 cells (ATCC CCL61), DXB-11, DG-44,and Chinese hamster ovary cells/−DHFR (CHO, Urlaub et al., Proc. Natl.Acad. Sci. USA 77: 4216, 1980); monkey kidney CV1 line transformed bySV40 (COS-7, ATCC CRL 1651); human embryonic kidney line (293 or 293cells subcloned for growth in suspension culture, (Graham et al., J. GenVirol. 36: 59, 1977); baby hamster kidney cells (BHK, ATCC CCL 10);mouse sertoli cells (TM4, Mather, Biol. Reprod. 23: 243-251, 1980);monkey kidney cells (CV1 ATCC CCL 70); African green monkey kidney cells(VERO-76, ATCC CRL-1587); human cervical carcinoma cells (HELA, ATCC CCL2); canine kidney cells (MDCK, ATCC CCL 34); buffalo rat liver cells(BRL 3A, ATCC CRL 1442); human lung cells (W138, ATCC CCL 75); humanhepatoma cells (Hep G2, HB 8065); mouse mammary tumor (MMT 060562, ATCCCCL51); TRI cells (Mather et al., Annals N.Y Acad. Sci. 383: 44-68,1982); MRC 5 cells or FS4 cells; mammalian myeloma cells, and a numberof other cell lines. In certain embodiments, cell lines may be selectedthrough determining which cell lines have high expression levels andconstitutively produce antibodies and antigen-binding fragments withPAC1 binding properties. In another embodiment, a cell line from the Bcell lineage that does not make its own antibody but has a capacity tomake and secrete a heterologous antibody can be selected. CHO cells arepreferred host cells in some embodiments for expressing the anti-PAC1antibodies and antigen-binding fragments of the invention.

Host cells are transformed or transfected with the above-describednucleic acids or vectors for production of anti-PAC1 antibodies orantigen-binding fragments and are cultured in conventional nutrientmedia modified as appropriate for inducing promoters, selectingtransformants, or amplifying the genes encoding the desired sequences.In addition, novel vectors and transfected cell lines with multiplecopies of transcription units separated by a selective marker areparticularly useful for the expression of antibodies and antigen-bindingfragments. Thus, the present invention also provides a method forproducing an anti-PAC1 antibody or antigen-binding fragment thereofdescribed herein comprising culturing a host cell comprising one or moreexpression vectors described herein in a culture medium under conditionspermitting expression of the antibody or antigen-binding fragmentencoded by the one or more expression vectors; and recovering theantibody or antigen-binding fragment from the culture medium or hostcell.

The host cells used to produce the antibodies or antigen-bindingfragments of the invention may be cultured in a variety of media.Commercially available media such as Ham's F10 (Sigma), MinimalEssential Medium (MEM, Sigma), RPMI-1640 (Sigma), and Dulbecco'sModified Eagle's Medium (DMEM, Sigma) are suitable for culturing thehost cells. In addition, any of the media described in Ham et al., Meth.Enz. 58: 44, 1979; Barnes et al., Anal. Biochem. 102: 255, 1980; U.S.Pat. Nos. 4,767,704; 4,657,866; 4,927,762; 4,560,655; or 5,122,469;WO90103430; WO 87/00195; or U.S. Pat. Re. No. 30,985 may be used asculture media for the host cells. Any of these media may be supplementedas necessary with hormones and/or other growth factors (such as insulin,transferrin, or epidermal growth factor), salts (such as sodiumchloride, calcium, magnesium, and phosphate), buffers (such as HEPES),nucleotides (such as adenosine and thymidine), antibiotics (such asGentamycin™ drug), trace elements (defined as inorganic compoundsusually present at final concentrations in the micromolar range), andglucose or an equivalent energy source. Any other necessary supplementsmay also be included at appropriate concentrations that would be knownto those skilled in the art. The culture conditions, such astemperature, pH, and the like, are those previously used with the hostcell selected for expression, and will be apparent to the ordinaryskilled artisan.

Upon culturing the host cells, the antibody or antigen-binding fragmentcan be produced intracellularly, in the periplasmic space, or directlysecreted into the medium. If the antibody or antigen-binding fragment isproduced intracellularly, as a first step, the particulate debris,either host cells or lysed fragments, is removed, for example, bycentrifugation or ultrafiltration. The antibody or antigen-bindingfragment can be purified using, for example, hydroxyapatitechromatography, cation or anion exchange chromatography, or preferablyaffinity chromatography, using the antigen(s) of interest or protein Aor protein G as an affinity ligand. Protein A can be used to purifyproteins that include polypeptides that are based on human γ1, γ2, or γ4heavy chains (Lindmark et al., J. Immunol. Meth. 62: 1-13, 1983).Protein G is recommended for all mouse isotypes and for human γ3 (Gusset al., EMBO J. 5: 1567-1575, 1986). The matrix to which the affinityligand is attached is most often agarose, but other matrices areavailable. Mechanically stable matrices such as controlled pore glass orpoly(styrenedivinyl)benzene allow for faster flow rates and shorterprocessing times than can be achieved with agarose. Where the proteincomprises a CH3 domain, the Bakerbond ABX™ resin (J. T. Baker,Phillipsburg, N.J.) is useful for purification. Other techniques forprotein purification such as ethanol precipitation, Reverse Phase HPLC,chromatofocusing, SDS-PAGE, and ammonium sulfate precipitation are alsopossible depending on the particular antibody or antigen-bindingfragment to be recovered.

In certain embodiments, the invention provides a composition (e.g. apharmaceutical composition) comprising one or a plurality of theanti-PAC1 antibodies or antigen-binding fragments of the invention (e.g.anti-PAC1 monoclonal antibodies or binding fragments thereof) togetherwith pharmaceutically acceptable diluents, carriers, excipients,solubilizers, emulsifiers, preservatives, and/or adjuvants. Thepharmaceutical compositions can be used in any of the methods describedherein. Pharmaceutical compositions of the invention include, but arenot limited to, liquid, frozen, and lyophilized compositions.“Pharmaceutically-acceptable” refers to molecules, compounds, andcompositions that are non-toxic to human recipients at the dosages andconcentrations employed and/or do not produce allergic or adversereactions when administered to humans. In some embodiments, thepharmaceutical composition may contain formulation materials formodifying, maintaining or preserving, for example, the pH, osmolarity,viscosity, clarity, color, isotonicity, odor, sterility, stability, rateof dissolution or release, adsorption or penetration of the composition.In such embodiments, suitable formulation materials include, but are notlimited to, amino acids (such as glycine, glutamine, asparagine,arginine or lysine); antimicrobials; antioxidants (such as ascorbicacid, sodium sulfite or sodium hydrogen-sulfite); buffers (such asborate, bicarbonate, Tris-HCl, citrates, phosphates or other organicacids); bulking agents (such as mannitol or glycine); chelating agents(such as ethylenediamine tetraacetic acid (EDTA)); complexing agents(such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin orhydroxypropyl-beta-cyclodextrin); fillers; monosaccharides;disaccharides; and other carbohydrates (such as glucose, mannose ordextrins); proteins (such as serum albumin, gelatin or immunoglobulins);coloring and diluting agents; emulsifying agents; hydrophilic polymers(such as polyvinylpyrrolidone); low molecular weight polypeptides;salt-forming counterions (such as sodium); preservatives (such asbenzalkonium chloride, benzoic acid, salicylic acid, thimerosal,phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbicacid or hydrogen peroxide); solvents (such as glycerin, propylene glycolor polyethylene glycol); sugar alcohols (such as mannitol or sorbitol);suspending agents; surfactants or wetting agents (such as pluronics,PEG, sorbitan esters, polysorbates such as polysorbate 20, polysorbate80, triton, tromethamine, lecithin, cholesterol, tyloxapal); stabilityenhancing agents (such as sucrose or sorbitol); tonicity enhancingagents (such as alkali metal halides, preferably sodium or potassiumchloride, mannitol sorbitol); delivery vehicles; diluents; excipientsand/or pharmaceutical adjuvants. Methods and suitable materials forformulating molecules for therapeutic use are known in thepharmaceutical arts, and are described, for example, in REMINGTON'SPHARMACEUTICAL SCIENCES, 18th Edition, (A. R. Genrmo, ed.), 1990, MackPublishing Company.

In some embodiments, the pharmaceutical composition of the inventioncomprises a standard pharmaceutical carrier, such as a sterile phosphatebuffered saline solution, bacteriostatic water, and the like. A varietyof aqueous carriers may be used, e.g., water, buffered water, 0.4%saline, 0.3% glycine and the like, and may include other proteins forenhanced stability, such as albumin, lipoprotein, globulin, etc.,subjected to mild chemical modifications or the like.

Exemplary concentrations of the antibodies or antigen-binding fragmentsin the formulation may range from about 0.1 mg/ml to about 200 mg/ml orfrom about 0.1 mg/mL to about 50 mg/mL, or from about 0.5 mg/mL to about25 mg/mL, or alternatively from about 2 mg/mL to about 10 mg/mL. Anaqueous formulation of the antibody or antigen-binding fragment may beprepared in a pH-buffered solution, for example, at pH ranging fromabout 4.5 to about 6.5, or from about 4.8 to about 5.5, or alternativelyabout 5.0. Examples of buffers that are suitable for a pH within thisrange include acetate (e.g. sodium acetate), succinate (such as sodiumsuccinate), gluconate, histidine, citrate and other organic acidbuffers. The buffer concentration can be from about 1 mM to about 200mM, or from about 10 mM to about 60 mM, depending, for example, on thebuffer and the desired isotonicity of the formulation.

A tonicity agent, which may also stabilize the antibody orantigen-binding fragment, may be included in the formulation. Exemplarytonicity agents include polyols, such as mannitol, sucrose or trehalose.Preferably the aqueous formulation is isotonic, although hypertonic orhypotonic solutions may be suitable. Exemplary concentrations of thepolyol in the formulation may range from about 1% to about 15% w/v.

A surfactant may also be added to the formulation to reduce aggregationof the formulated antibody or antigen-binding fragment and/or minimizethe formation of particulates in the formulation and/or reduceadsorption. Exemplary surfactants include nonionic surfactants such aspolysorbates (e.g. polysorbate 20 or polysorbate 80) or poloxamers (e.g.poloxamer 188). Exemplary concentrations of surfactant may range fromabout 0.001% to about 0.5%, or from about 0.005% to about 0.2%, oralternatively from about 0.004% to about 0.01% w/v.

In one embodiment, the formulation contains the above-identified agents(i.e. antibody or antigen-binding fragment, buffer, polyol andsurfactant) and is essentially free of one or more preservatives, suchas benzyl alcohol, phenol, m-cresol, chlorobutanol and benzethoniumchloride. In another embodiment, a preservative may be included in theformulation, e.g., at concentrations ranging from about 0.1% to about2%, or alternatively from about 0.5% to about 1%. One or more otherpharmaceutically acceptable carriers, excipients or stabilizers such asthose described in REMINGTON'S PHARMACEUTICAL SCIENCES, 18th Edition,(A. R. Genrmo, ed.), 1990, Mack Publishing Company, may be included inthe formulation provided that they do not adversely affect the desiredcharacteristics of the formulation.

Therapeutic formulations of the antibody or antigen-binding fragment areprepared for storage by mixing the antibody or antigen-binding fragmenthaving the desired degree of purity with optional physiologicallyacceptable carriers, excipients or stabilizers (REMINGTON'SPHARMACEUTICAL SCIENCES, 18th Edition, (A. R. Genrmo, ed.), 1990, MackPublishing Company), in the form of lyophilized formulations or aqueoussolutions. Acceptable carriers, excipients, or stabilizers are nontoxicto recipients at the dosages and concentrations employed, and includethose described above, such as buffers (e.g. phosphate, citrate, andother organic acids); antioxidants (e.g. ascorbic acid and methionine);preservatives (such as octadecyldimethylbenzyl ammonium chloride,hexamethonium chloride, benzalkonium chloride, benzethonium chloride,phenol, butyl or benzyl alcohol, alkyl parabens such as methyl or propylparaben, catechol; resorcinol, cyclohexanol, 3-pentanol, and m-cresol);low molecular weight (e.g. less than about 10 residues) polypeptides;proteins (such as serum albumin, gelatin, or immunoglobulins);hydrophilic polymers (e.g. polyvinylpyrrolidone); amino acids (e.g.glycine, glutamine, asparagine, histidine, arginine, or lysine);monosaccharides, disaccharides, and other carbohydrates includingglucose, mannose, maltose, or dextrins; chelating agents such as EDTA;sugars such as sucrose, mannitol, trehalose or sorbitol; salt-formingcounter-ions such as sodium; metal complexes (e.g., Zn-proteincomplexes); and/or non-ionic surfactants, such as polysorbates (e.g.polysorbate 20 or polysorbate 80) or poloxamers (e.g. poloxamer 188); orpolyethylene glycol (PEG).

In one embodiment, a suitable formulation of the invention contains anisotonic buffer such as a phosphate, acetate, or TRIS buffer incombination with a tonicity agent, such as a polyol, sorbitol, sucroseor sodium chloride, which tonicities and stabilizes. One example of sucha tonicity agent is 5% sorbitol or sucrose. In addition, the formulationcould optionally include a surfactant at 0.01% to 0.02% wt/vol, forexample, to prevent aggregation or improve stability. The pH of theformulation may range from 4.5 to 6.5 or 4.5 to 5.5. Other exemplarydescriptions of pharmaceutical formulations for antibodies andantigen-binding fragments may be found in US Patent Publication No.2003/0113316 and U.S. Pat. No. 6,171,586, each of which is herebyincorporated by reference in its entirety.

The formulations to be used for in vivo administration must be sterile.The compositions of the invention may be sterilized by conventional,well-known sterilization techniques. For example, sterilization isreadily accomplished by filtration through sterile filtration membranes.The resulting solutions may be packaged for use or filtered underaseptic conditions and lyophilized, the lyophilized preparation beingcombined with a sterile solution prior to administration.

The process of freeze-drying is often employed to stabilize polypeptidesfor long-term storage, particularly when the polypeptide is relativelyunstable in liquid compositions. A lyophilization cycle is usuallycomposed of three steps: freezing, primary drying, and secondary drying(see Williams and Polli, Journal of Parenteral Science and Technology,Volume 38, Number 2, pages 48-59, 1984). In the freezing step, thesolution is cooled until it is adequately frozen. Bulk water in thesolution forms ice at this stage. The ice sublimes in the primary dryingstage, which is conducted by reducing chamber pressure below the vaporpressure of the ice, using a vacuum. Finally, sorbed or bound water isremoved at the secondary drying stage under reduced chamber pressure andan elevated shelf temperature. The process produces a material known asa lyophilized cake. Thereafter the cake can be reconstituted prior touse. The standard reconstitution practice for lyophilized material is toadd back a volume of pure water (typically equivalent to the volumeremoved during lyophilization), although dilute solutions ofantibacterial agents are sometimes used in the production ofpharmaceuticals for parenteral administration (see Chen, DrugDevelopment and Industrial Pharmacy, Volume 18: 1311-1354, 1992).

Excipients have been noted in some cases to act as stabilizers forfreeze-dried products (see Carpenter et al., Volume 74: 225-239, 1991).For example, known excipients include polyols (including mannitol,sorbitol and glycerol); sugars (including glucose and sucrose); andamino acids (including alanine, glycine and glutamic acid). In addition,polyols and sugars are also often used to protect polypeptides fromfreezing- and drying-induced damage and to enhance the stability duringstorage in the dried state. In general, sugars, in particulardisaccharides, are effective in both the freeze-drying process andduring storage. Other classes of molecules, including mono- anddi-saccharides and polymers such as PVP, have also been reported asstabilizers of lyophilized products.

For injection, the pharmaceutical formulation and/or medicament may be apowder suitable for reconstitution with an appropriate solution asdescribed above. Examples of these include, but are not limited to,freeze dried, rotary dried or spray dried powders, amorphous powders,granules, precipitates, or particulates. For injection, the formulationsmay optionally contain stabilizers, pH modifiers, surfactants,bioavailability modifiers and combinations of these.

Sustained-release preparations may be prepared. Suitable examples ofsustained-release preparations include semipermeable matrices of solidhydrophobic polymers containing the antibody or antigen-bindingfragment, which matrices are in the form of shaped articles, e.g.,films, or microcapsule. Examples of sustained-release matrices includepolyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate),or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919),copolymers of L-glutamic acid and y ethyl-L-glutamate, non-degradableethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymerssuch as the Lupron Depot™ (injectable microspheres composed of lacticacid-glycolic acid copolymer and leuprolide acetate), andpoly-D-(−)-3-hydroxybutyric acid. While polymers such as ethylene-vinylacetate and lactic acid-glycolic acid enable release of molecules forover 100 days, certain hydrogels release proteins for shorter timeperiods. When encapsulated polypeptides remain in the body for a longtime, they may denature or aggregate as a result of exposure to moistureat 37° C., resulting in a loss of biological activity and possiblechanges in immunogenicity. Rational strategies can be devised forstabilization depending on the mechanism involved. For example, if theaggregation mechanism is discovered to be intermolecular S—S bondformation through thio-disulfide interchange, stabilization may beachieved by modifying sulfhydryl residues, lyophilizing from acidicsolutions, controlling moisture content, using appropriate additives,and developing specific polymer matrix compositions.

The formulations of the invention may be designed to be short-acting,fast-releasing, long-acting, or sustained-releasing as described herein.Thus, the pharmaceutical formulations may also be formulated forcontrolled release or for slow release.

Specific dosages may be adjusted depending on the disease, disorder, orcondition to be treated (e.g. episodic migraine, chronic migraine, orcluster headache), the age, body weight, general health conditions, sex,and diet of the subject, dose intervals, administration routes,excretion rate, and combinations of drugs.

The anti-PAC1 antibodies or antigen-binding fragments of the inventioncan be administered by any suitable means, including parenteral,subcutaneous, intravenous, intraperitoneal, intrapulmonary, andintranasal, and, if desired for local treatment, intralesionaladministration. Parenteral administration includes intravenous,intraarterial, intraperitoneal, intramuscular, intradermal orsubcutaneous administration. In addition, the antibody orantigen-binding fragment is suitably administered by pulse infusion,particularly with declining doses of the antibody or antigen-bindingfragment. Preferably, the dosing is given by injections, most preferablyintravenous or subcutaneous injections, depending in part on whether theadministration is brief or chronic. Other administration methods arecontemplated, including topical, particularly transdermal, transmucosal,rectal, oral or local administration e.g. through a catheter placedclose to the desired site. The antibody or antigen-binding fragment ofthe invention may be administered in a physiological solution at a doseranging between 0.01 mg/kg to 100 mg/kg at a frequency ranging fromdaily to weekly to monthly.

The anti-PAC1 antibodies and antigen-binding fragments described hereinare useful for treating or ameliorating a condition associated with thebiological activity of the PAC1 receptor in a patient in need thereof.Thus, anti-PAC1 antibodies and antigen-binding fragments of theinvention for use in methods of treatment are disclosed herein. The term“patient” includes human patients and is used interchangeably with theterm “subject.” As used herein, the term “treating” or “treatment” is anintervention performed with the intention of preventing the developmentor altering the pathology of a disorder. Accordingly, “treatment” refersto both therapeutic treatment and prophylactic or preventative measures.Those in need of treatment include those already diagnosed with orsuffering from the disorder or condition as well as those in which thedisorder or condition is to be prevented. “Treatment” includes anyindicia of success in the amelioration of an injury, pathology orcondition, including any objective or subjective parameter such asabatement, remission, diminishing of symptoms, or making the injury,pathology or condition more tolerable to the patient, slowing in therate of degeneration or decline, making the final point of degenerationless debilitating, or improving a patient's physical or mentalwell-being. The treatment or amelioration of symptoms can be based onobjective or subjective parameters, including the results of a physicalexamination, self-reporting by a patient, neuropsychiatric exams, and/ora psychiatric evaluation.

Accordingly, in some embodiments, the present invention provides amethod for treating or preventing a condition associated with thebiological activity of the PAC1 receptor (e.g. a condition associatedwith PACAP-induced activation of the PAC1 receptor) in a patient in needthereof, comprising administering to the patient an effective amount ofan anti-PAC1 antibody or antigen-binding fragment thereof describedherein. The PACAP/PAC1 signaling pathway has been implicated in variousphysiological processes, including cardiovascular function, metabolicand endocrine function, inflammation, stress response, regulation ofvasomotor tone, and regulation of the autonomic nervous system,particularly the balance between the sympathetic and parasympatheticsystems. See, e.g., Tanida et al., Regulatory Peptides, Vol. 161: 73-80,2010; Moody et al., Curr. Opin. Endocrinol. Diabetes Obes., Vol. 18:61-67, 2011; and Hashimoto et al., Current Pharmaceutical Design, Vol.17: 985-989, 2011. Conditions associated with aberrant or overactivationof the PACAP/PAC1 signaling pathway include, but are not limited to,headache conditions, such as migraine, cluster headache, tension-typeheadache, hemiplegic migraine, and retinal migraine; inflammatory skinconditions; chronic pain, such as neuropathic pain; anxiety disorders;irritable bowel syndrome; and vasomotor symptoms, such as hot flashes,facial flushing, sweating, and night sweats. Thus, the anti-PAC1antibodies and antigen-binding fragments thereof of the invention can beadministered to patients to prevent, ameliorate, or treat any of theseconditions or disorders or other conditions associated with aberrant orexcessive PAC1 receptor biological activity. In certain embodiments, thepresent invention provides methods for treating or preventing a headachecondition (e.g. episodic migraine, chronic migraine, cluster headache,tension-type headache, hemiplegic migraine, and retinal migraine) in apatient in need thereof comprising administering to the patient aneffective amount of an anti-PAC1 antibody or antigen-binding fragmentthereof as described herein. In some embodiments, the present inventionprovides a method for inhibiting activation of the human PAC1 receptorin a patient having a headache condition comprising administering to thepatient an effective amount of an anti-PAC1 antibody or antigen-bindingfragment thereof described herein. In one embodiment, the patient has amigraine headache condition, such as episodic migraine or chronicmigraine. In another embodiment, the patient has a cluster headachecondition.

An “effective amount” is generally an amount sufficient to reduce theseverity and/or frequency of symptoms, eliminate the symptoms and/orunderlying cause, prevent the occurrence of symptoms and/or theirunderlying cause, and/or improve or remediate the damage that resultsfrom or is associated with a particular condition. In some embodiments,the effective amount is a therapeutically effective amount or aprophylactically effective amount. A “therapeutically effective amount”is an amount sufficient to remedy a disease state or symptom(s),particularly a state or symptom(s) associated with the disease state, orotherwise prevent, hinder, retard or reverse the progression of thedisease state or any other undesirable symptom associated with thedisease in any way whatsoever (i.e. that provides “therapeuticefficacy”). A “prophylactically effective amount” is an amount of anantibody or antigen-binding fragment that, when administered to asubject, will have the intended prophylactic effect, e.g., preventing ordelaying the onset (or reoccurrence) of the condition, or reducing thelikelihood of the onset (or reoccurrence) of the condition. The fulltherapeutic or prophylactic effect does not necessarily occur byadministration of one dose, and may occur only after administration of aseries of doses. Thus, a therapeutically or prophylactically effectiveamount may be administered in one or more administrations.

In certain embodiments, the present invention provides methods forinhibiting vasodilation in a patient in need thereof comprisingadministering to the patient an effective amount of an anti-PAC1antibody or antigen-binding fragment thereof described herein. Ligandsof the PAC1 receptor, such as PACAP38 and VIP, are potent vasodilators,and blocking the binding of these ligands to the PAC1 receptor caninhibit vasodilation and ameliorate conditions associated with aberrantor excessive vasodilation, such as headache conditions, hot flashes, andflushing. In one embodiment, the patient has a headache condition, suchas migraine or cluster headache. In another embodiment, the patient hasvasomotor symptoms (e.g. hot flashes, facial flushing, sweating, ornight sweats). In a related embodiment, the patient has vasomotorsymptoms associated with menopause.

In some embodiments of the methods of the invention, the headachecondition to be treated, prevented or ameliorated is migraine. Thus, thepresent invention includes a method for treating, preventing, orameliorating migraine in a patient in need thereof comprisingadministering to the patient an effective amount of an anti-PAC1antibody or antigen-binding fragment thereof described herein. Migraineheadaches are recurrent headaches lasting about 4 to about 72 hours thatare characterized by unilateral, pulsating, and/or moderate to severepain and/or pain that is exacerbated by physical activity. Migraineheadaches are often accompanied by nausea, vomiting, and/or sensitivityto light (photophobia), sound (phonophobia), or smell. In some patients,an aura precedes the onset of the migraine headache. The aura istypically a visual, sensory, language, or motor disturbance that signalsthe headache will soon occur. The methods described herein prevent,treat, or ameliorate one or more symptoms of migraine headaches with andwithout aura in human patients.

PACAP38, through activation of its receptors, induces vasodilation,particularly vasodilation of the dura vasculature (Schytz et al.,Neurotherapeutics, Vol. 7(2):191-196, 2010). The PACAP38/PAC1 receptorsignaling cascade, in particular, has been implicated in migrainepathophysiology (Amin et al., Brain, Vol. 137: 779-794, 2014). Infusionof PACAP38, which has a higher affinity for the PAC1 receptor than theVPAC1 and VPAC2 receptors, causes migraine-like headache in migrainepatients (Schytz et al., Brain 132:16-25, 2009; Amin et al., Brain, Vol.137: 779-794, 2014; Guo et al., Cephalalgia, Vol. 37:125-135, 2017). Inaddition, PACAP38 levels are elevated in cranial circulation in patientsexperiencing a migraine attack, and the PACAP38 levels are reducedfollowing treatment of the migraine symptoms with triptans (Tuka et al.,Cephalalgia, Vol. 33, 1085-1095, 2013; Zagami et al., Ann. Clin. Transl.Neurol., Vol. 1: 1036-1040, 2014). These reports suggest that endogenousrelease of PACAP38 is an important trigger of migraine headache and itseffects are primarily mediated through activation of the PAC1 receptor.

In some embodiments, the patients to be treated according to the methodsof the invention have, suffer from, or are diagnosed with episodicmigraine. Episodic migraine is diagnosed when patients with a history ofmigraine (e.g. at least five lifetime attacks of migraine headache) have14 or fewer migraine headache days per month. A “migraine headache day”includes any calendar day during which a patient experiences the onset,continuation, or recurrence of a “migraine headache” with or withoutaura lasting greater than 30 minutes. A “migraine headache” is aheadache associated with nausea or vomiting or sensitivity to light orsound and/or a headache characterized by at least two of the followingpain features: unilateral pain, throbbing pain, moderate to severe painintensity, or pain exacerbated by physical activity. In certainembodiments, patients having, suffering from, or diagnosed with episodicmigraine have at least four, but less than 15 migraine headache days permonth on average. In related embodiments, patients having, sufferingfrom, or diagnosed with episodic migraine have fewer than 15 headachedays per month on average. As used herein, a “headache day” is anycalendar day in which the patient experiences a migraine headache asdefined herein or any headache that lasts greater than 30 minutes orrequires acute headache treatment.

In certain embodiments, the patients to be treated according to themethods of the invention have, suffer from, or are diagnosed withchronic migraine. Chronic migraine is diagnosed when migraine patients(i.e. patients with at least five lifetime attacks of migraine headache)have 15 or more headache days per month and at least 8 of the headachedays are migraine headache days. In some embodiments, patients having,suffering from, or diagnosed with chronic migraine have 15 or moremigraine headache days per month on average. In certain embodiments ofthe methods described herein, administration of an anti-PAC1 antibody orantigen-binding fragment of the invention prevents, reduces, or delaysthe progression of episodic migraine to chronic migraine in the patient.

In some embodiments, the present invention provides a method fortreating, preventing, or ameliorating cluster headache in a patient inneed thereof comprising administering to the patient an effective amountof an anti-PAC1 antibody or antigen-binding fragment thereof describedherein. Cluster headache is a condition that involves, as its mostprominent feature, recurrent, severe headaches on one side of the head,typically around the eye (see Nesbitt et al., BMJ, Vol. 344:e2407,2012). Cluster headaches often occur periodically: spontaneousremissions interrupt active periods of pain. Cluster headaches are oftenaccompanied by cranial autonomic symptoms, such as tearing, nasalcongestion, ptosis, pupil constriction, facial blushing, sweating, andswelling around the eye, often confined to the side of the head with thepain. The average age of onset of cluster headache is ˜30-50 years. Itis more prevalent in males with a male to female ratio of about 2.5:1 toabout 3.5:1. Sphenopalatine ganglion (SPG) stimulation has been used forthe treatment of cluster headache. A neurostimulation system, whichdelivers low-level (but high frequency, physiologic-blocking) electricalstimulation to the SPG, has demonstrated efficacy in relieving the acutedebilitating pain of cluster headache in a recent clinical trial (seeSchoenen J, et al., Cephalalgia, Vol. 33(10):816-30, 2013). In view ofthis evidence and because PACAP is one of the major neurotransmitters inSPG, inhibition of PACAP/PAC1 signaling with an anti-PAC1 antibody orantigen-binding fragment thereof described herein is expected to haveefficacy in treating cluster headache in humans.

Other conditions associated with the PACAP/PAC1 signaling pathway thatmay be treated according to the methods of the invention include, butare not limited to, inflammatory skin conditions, such as rosacea (seeU.S. Patent Publication No. 20110229423), chronic pain syndromes, suchas neuropathic pain (see Jongsma et al., Neuroreport, Vol. 12:2215-2219, 2001; Hashimoto et al., Annals of the New York Academy ofSciences, Vol. 1070: 75-89, 2006), tension-type headaches, hemiplegicmigraine, retinal migraine, anxiety disorders, such as posttraumaticstress disorder (see Hammack and May, Biol. Psychiatry, Vol.78(3):167-177, 2015), irritable bowel syndrome, and vasomotor symptoms(e.g. hot flashes, facial flushing, sweating, and night sweats), such asthose associated with menopause. In one embodiment, the condition to betreated by administering an anti-PAC1 antibody or antigen-bindingfragment thereof of the invention is chronic pain. In anotherembodiment, the condition to be treated by administering an anti-PAC1antibody or antigen-binding fragment thereof of the invention isneuropathic pain.

In any of the methods described herein, the treatment can compriseprophylactic treatment. Prophylactic treatment refers to treatmentdesigned to be taken before the onset of a condition or an attack (e.g.before a migraine attack or onset of a cluster headache episode) toreduce the frequency, severity, and/or length of the symptoms (e.g.migraine or cluster headaches) in the patient.

In some embodiments, the methods of the invention for treating orpreventing a headache condition in a patient comprise administering tothe patient an anti-PAC1 antibody or antigen-binding fragment thereofdescribed herein in combination with one or more agents suitable for theacute or prophylactic treatment of migraine headache or other headachedisorder described herein. The term “combination therapy” as used hereinencompasses the administration of the two compounds (e.g. anti-PAC1antibody and additional agent) in a sequential manner (i.e. eachcompound is administered at a different time in any order) as well asadministration of the two compounds in a substantially simultaneousmanner. Substantially simultaneous administration includes concurrentadministration and can be accomplished by administering a singleformulation comprising both compounds (e.g. a single formulationcomprising a fixed ratio of both compounds or a pre-filled syringehaving a fixed ratio of each compound) or concurrently administeringseparate formulations containing each of the compounds. Thus, in certainembodiments, the methods of the invention comprise administering ananti-PAC1 antibody or antigen-binding fragment thereof described hereinwith a second headache therapeutic agent.

In certain embodiments, the second headache therapeutic agent may be anacute headache therapeutic agent used for the acute treatment ofheadaches or migraines. In some embodiments, the acute headachetherapeutic agent is a serotonin (5-hydroxytryptamine; 5-HT) receptoragonist, for example a 5HT1 receptor agonist. The acute headachetherapeutic agent can be an agonist of the 5HT_(1B), 5HT_(1D) and/or5HT_(1F) serotonin receptors. Such serotonin receptor agonists include,but are not limited to, triptans (e.g., almotriptan, frovatriptan,rizatriptan, sumatriptan, naratriptan, eletriptan, and zolmitriptan),ergotamines (e.g., dihydroergotamine and ergotamine tartrate), and5HT_(1F)-selective serotonin receptor agonists, such as lasmiditan.Other suitable acute headache therapeutic agents include non-steroidalanti-inflammatory drugs (e.g., acetylsalicylic acid, ibuprofen,naproxen, indomethacin, and diclofenac), and opioids (e.g., codeine,morphine, hydrocodone, fentanyl, meperidine, and oxycodone). In oneembodiment, the acute headache therapeutic agent administered incombination with an anti-PAC1 antibody or antigen-binding fragment ofthe invention is a triptan. In another embodiment, the acute headachetherapeutic agent administered in combination with an anti-PAC1 antibodyor antigen-binding fragment of the invention is an ergotamine. In yetanother embodiment, the acute headache therapeutic agent administered incombination with an anti-PAC1 antibody or antigen-binding fragment ofthe invention is a non-steroidal anti-inflammatory drug. In stillanother embodiment, the acute headache therapeutic agent administered incombination with an anti-PAC1 antibody or antigen-binding fragment ofthe invention is an opioid.

In some embodiments, the second headache therapeutic agent is aprophylactic headache therapeutic agent used for the prophylactictreatment of headaches or migraines. In one embodiment, the prophylacticheadache therapeutic agent is an antiepileptic, such as divalproex,sodium valproate, valproic acid, topiramate, or gabapentin. In anotherembodiment, the prophylactic headache therapeutic agent is abeta-blocker, such as propranolol, timolol, atenolol, metoprolol, ornadolol. In yet another embodiment, the prophylactic headachetherapeutic agent is an anti-depressant, such as a tricyclicantidepressant (e.g. amitriptyline, nortriptyline, doxepin, andfluoxetine). In still another embodiment, the prophylactic headachetherapeutic agent is onabotulinum toxin A.

In certain embodiments, the methods of the invention compriseadministering an anti-PAC1 antibody or antigen-binding fragment thereofdescribed herein with an antagonist of the calcitonin gene-relatedpeptide (CGRP) signaling pathway (i.e. inhibits the activation orsignaling of the CGRP receptor by the CGRP ligand). For example, theanti-PAC1 antibody or antigen-binding fragment of the invention can beadministered in combination with a CGRP pathway antagonist to treat orprevent a headache condition (e.g. migraine or cluster headache) in apatient in need thereof. In some embodiments, the CGRP pathwayantagonist is an antagonist of the human CGRP receptor. CGRP receptorantagonists include small molecule inhibitors of the CGRP receptor, suchas those described in U.S. Patent Publication No. 20060142273 and U.S.Pat. Nos. 7,842,808; 7,772,244; 7,754,732; 7,569,578; 8,685,965;8,569,291; 8,377,955; 8,372,859; 8,143,266; 7,947,677; and 7,625,901,all of which are hereby incorporated by reference in their entireties.CGRP receptor antagonists can also include peptide antagonists of thereceptor, such as those described in U.S. Pat. No. 8,168,592, which ishereby incorporated by reference in its entirety. In certainembodiments, the CGRP receptor antagonist to be administered with theanti-PAC1 antibodies and antigen-binding fragments of the invention is amonoclonal antibody that specifically binds to the human CGRP receptor,such as the antibodies described in U.S. Pat. No. 9,102,731 and U.S.Patent Publication No. 20160311913, both of which are herebyincorporated by reference in their entireties. In one particularembodiment of the methods of the invention, an anti-PAC1 antibody orantigen-binding fragment thereof described herein is administered incombination with an anti-CGRP receptor monoclonal antibody comprising alight chain variable region comprising the sequence of SEQ ID NO: 502(sequence provided below) and a heavy chain variable region comprisingthe sequence of SEQ ID NO: 503 (sequence provided below) to treat orprevent a headache condition (e.g. migraine or cluster headache) in apatient. In another particular embodiment of the methods of theinvention, the anti-CGRP receptor monoclonal antibody administered incombination with the anti-PAC1 antibody or antigen-binding fragment ofthe invention to treat or prevent a headache condition (e.g. migraine orcluster headache) in a patient is erenumab.

Light chain variable region sequence for exemplary anti-CGRP receptormonoclonal antibody:

(SEQ ID NO: 502) QSVLTQPPSV SAAPGQKVTI SCSGSSSNIG NNYVSWYQQLPGTAPKLLIY DNNKRPSGIP DRFSGSKSGT STTLGITGLQTGDEADYYCG TWDSRLSAVV FGGGTKLTVL

Heavy chain variable region sequence for exemplary anti-CGRP receptormonoclonal antibody:

(SEQ ID NO: 503) QVQLVESGGG VVQPGRSLRL SCAASGFTFS SFGMHWVRQAPGKGLEWVAV ISFDGSIKYS VDSVKGRFTI SRDNSKNTLFLQMNSLRAED TAVYYCARDR LNYYDSSGYY HYKYYGMAVW GQGTTVTVSS

In some embodiments, the CGRP pathway antagonist to be administered withthe anti-PAC1 antibody or antigen-binding fragment of the invention totreat or prevent a headache condition (e.g. migraine or clusterheadache) in a patient is an antagonist of the CGRP ligand. A CGRPligand antagonist can be a decoy or soluble CGRP receptor or otherprotein that binds to the CGRP ligand, such as an anti-CGRP ligandantibody. Anti-CGRP ligand antibodies are known in the art and aredescribed, for example, in WO 2007/054809; WO 2007/076336; WO2011/156324; and WO 2012/162243, all of which are hereby incorporated byreference in their entireties. In certain embodiments, the CGRP ligandantagonist to be administered with the anti-PAC1 antibodies andantigen-binding fragments of the invention is a monoclonal antibody thatspecifically binds to human α-CGRP and/or human β-CGRP. In oneembodiment, the anti-CGRP ligand antibody is fremanezumab. In anotherembodiment, the anti-CGRP ligand antibody is galcanezumab. In yetanother embodiment, the anti-CGRP ligand antibody is eptinezumab.

The present invention also includes the use of anti-PAC1 antibodies andantigen-binding fragments in any of the methods disclosed herein. Forinstance, in certain embodiments, the present invention provides ananti-PAC1 antibody or antigen-binding fragment thereof described hereinfor use in a method for treating or preventing a headache condition in apatient in need thereof. In some such embodiments, the headachecondition is migraine. The migraine may be episodic migraine or chronicmigraine. In other embodiments, the headache condition is clusterheadache. In some embodiments, the method for treating or preventing aheadache condition comprises administering a second headache therapeuticagent in combination with the anti-PAC1 antibody or antigen-bindingfragment thereof. In one embodiment, the second headache therapeuticagent is an acute headache therapeutic agent, such as a 5HT_(1B),5HT_(1D) and/or 5HT_(1F) serotonin receptor agonist (e.g. a triptan orergotamine), a non-steroidal anti-inflammatory drug, or an opioid. Inanother embodiment, the second headache therapeutic agent is aprophylactic headache therapeutic agent, such as an antiepileptic, abeta-blocker, an anti-depressant, onabotulinum toxin A, or a CGRPpathway antagonist. In some embodiments, the CGRP pathway antagonist isa human CGRP receptor antagonist. In one particular embodiment, thehuman CGRP receptor antagonist is a monoclonal antibody thatspecifically binds to the human CGRP receptor, such as erenumab. Inother embodiments, the CGRP pathway antagonist is an antagonist of theCGRP ligand, such as a monoclonal antibody that specifically binds tohuman α-CGRP and/or human β-CGRP. In certain embodiments, the anti-CGRPligand antibody is fremanezumab, galcanezumab, or eptinezumab.

In some embodiments, the present invention provides an anti-PAC1antibody or antigen-binding fragment described herein for use in amethod for inhibiting vasodilation in a patient in need thereof. In suchembodiments, the patient may be diagnosed with or have a headachecondition, such as migraine (e.g. episodic or chronic migraine) orcluster headache. In other embodiments, the present invention providesan anti-PAC1 antibody or antigen-binding fragment described herein foruse in a method for inhibiting activation of human PAC1 receptor in apatient having a headache condition. The headache condition may bemigraine (e.g. episodic or chronic migraine) or cluster headache.

The use of anti-PAC1 antibodies or antigen-binding fragments thereof forpreparation of medicaments for administration according to any of themethods disclosed herein is specifically contemplated. For example, insome embodiments, the present invention encompasses the use of ananti-PAC1 antibody or antigen-binding fragment described herein in thepreparation of a medicament for treating or preventing a headachecondition in a patient in need thereof. In some such embodiments, theheadache condition is migraine. The migraine may be episodic migraine orchronic migraine. In other embodiments, the headache condition iscluster headache. In certain embodiments, the anti-PAC1 antibody orantigen-binding fragment thereof is formulated for administration with asecond headache therapeutic agent. In one embodiment, the secondheadache therapeutic agent is an acute headache therapeutic agent, suchas a 5HT_(1B), 5HT_(1D) and/or 5HT_(1F) serotonin receptor agonist (e.g.a triptan or ergotamine), a non-steroidal anti-inflammatory drug, or anopioid. In another embodiment, the second headache therapeutic agent isa prophylactic headache therapeutic agent, such as an antiepileptic, abeta-blocker, an anti-depressant, onabotulinum toxin A, or a CGRPpathway antagonist. In some embodiments, the CGRP pathway antagonist isa human CGRP receptor antagonist. In one particular embodiment, thehuman CGRP receptor antagonist is a monoclonal antibody thatspecifically binds to the human CGRP receptor, such as erenumab. Inother embodiments, the CGRP pathway antagonist is an antagonist of theCGRP ligand, such as a monoclonal antibody that specifically binds tohuman α-CGRP and/or human β-CGRP. In certain embodiments, the anti-CGRPligand antibody is fremanezumab, galcanezumab, or eptinezumab.

In some embodiments, the present invention includes the use of ananti-PAC1 antibody or antigen-binding fragment described herein in thepreparation of a medicament for inhibiting vasodilation in a patient inneed thereof. In such embodiments, the patient may be diagnosed with orhave a headache condition, such as migraine (e.g. episodic or chronicmigraine) or cluster headche. In other embodiments, the presentinvention includes the use of an anti-PAC1 antibody or antigen-bindingfragment described herein in the preparation of a medicament forinhibiting activation of human PAC1 receptor in a patient having aheadache condition. The headache condition may be migraine (e.g.episodic or chronic migraine) or cluster headache.

The anti-PAC1 antibodies and antigen-binding fragments of the inventionare also useful for detecting human PAC1 in biological samples andidentification of cells or tissues that express human PAC1. Forinstance, the anti-PAC1 antibodies and antigen-binding fragments can beused in diagnostic assays, e.g., immunoassays to detect and/or quantifyPAC1 expressed in a tissue or cell. In addition, the anti-PAC1antibodies and antigen-binding fragments described herein can be used toinhibit PAC1 from forming a complex with PACAP, thereby modulating thebiological activity of PAC1 in a cell or tissue. Such biologicalactivity includes elevation of intracellular cAMP and vasodilation.

The anti-PAC1 antibodies and antigen-binding fragments described hereincan be used for diagnostic purposes to detect, diagnose, or monitordiseases and/or conditions associated with PAC1, including migraine,cluster headache, and anxiety disorders, such as posttraumatic stressdisorder. Also provided are methods for the detection of the presence ofPAC1 in a sample using classical immunohistological methods known tothose of skill in the art (e.g., Tijssen, 1993, Practice and Theory ofEnzyme Immunoassays, Vol 15 (Eds R. H. Burdon and P. H. van Knippenberg,Elsevier, Amsterdam); Zola, 1987, Monoclonal Antibodies: A Manual ofTechniques, pp. 147-158 (CRC Press, Inc.); Jalkanen et al., 1985, J.Cell. Biol. 101:976-985; Jalkanen et al., 1987, J. Cell Biol.105:3087-3096). Examples of methods useful in the detection of thepresence of PAC1 include immunoassays, such as the enzyme linkedimmunosorbent assay (ELISA) and the radioimmunoassay (RIA), using theanti-PAC1 antibodies and antigen-binding fragments described herein. Thedetection of PAC1 can be performed in vivo or in vitro.

For diagnostic applications, the anti-PAC1 antibody or antigen-bindingfragment can be labeled with a detectable labeling group. Suitablelabeling groups include, but are not limited to, the following:radioisotopes or radionuclides (e.g., ³H, ¹⁴C, ¹⁵N, ³⁵S, ⁹⁰Y, ⁹⁹Tc,¹¹¹In, ¹²⁵I, ¹³¹I), fluorescent groups (e.g., FITC, rhodamine,lanthanide phosphors), enzymatic groups (e.g., horseradish peroxidase,β-galactosidase, luciferase, alkaline phosphatase), chemiluminescentgroups, biotinyl groups, or predetermined polypeptide epitopesrecognized by a secondary reporter (e.g., leucine zipper pair sequences,binding sites for secondary antibodies, metal binding domains, epitopetags). In some embodiments, the labeling group is coupled to theantibody or antigen-binding fragment via spacer arms of various lengthsto reduce potential steric hindrance. Various methods for labelingproteins are known in the art and may be used.

In another embodiment, the anti-PAC1 antibodies and antigen-bindingfragments described herein can be used to identify a cell or cells thatexpress PAC1. In a specific embodiment, the antibody or antigen-bindingfragment is labeled with a labeling group and the binding of the labeledantibody or antigen-binding fragment to PAC1 is detected. The antibodiesor antigen-binding fragments can also be used in immunoprecipitationassays in biological samples. In a further specific embodiment, thebinding of the antibody or antigen-binding fragment to PAC1 is detectedin vivo. In a further specific embodiment, the antibody orantigen-binding fragment is isolated and measured using techniques knownin the art. See, for example, Harlow and Lane, 1988, Antibodies: ALaboratory Manual, New York: Cold Spring Harbor (ed. 1991 and periodicsupplements); John E. Coligan, ed., 1993, Current Protocols InImmunology New York: John Wiley & Sons.

The following examples, including the experiments conducted and theresults achieved, are provided for illustrative purposes only and arenot to be construed as limiting the scope of the appended claims.

EXAMPLES Example 1. Crystal Structure-Guided Design of Human PAC1Antibodies

The crystal structure of a complex between the extracellular domain(ECD) of human PAC1 and the Fab fragment of a human anti-PAC1neutralizing antibody (29G4v9) was determined. The human PAC1 ECD andanti-PAC1 Fab were separately purified and then complexed together in1:1 molar ratio. The sample was subsequently run over gel filtrationcolumn equilibrated in 20 mM TRIS pH 7.5, 50 mM NaCl, 5 mM EDTA andconcentrated to 35 mg/ml and filtered.

The sequences for the heavy chain (comprising the variable region (VH),CH1 constant region, upper hinge, and caspase III cleavage site) and thelight chain (comprising the variable region (VL) and CL constant region)of the Fab fragment are listed below. The sequence of the human PAC1 ECDconstruct is provided below and contained amino acids 26 to 143 of humanPAC1 (SEQ ID NO: 1) minus the region between amino acids 89-109.

Amino acid sequence for heavy chain of 29G4v9 Fab (comprised of VHregion (amino acids: 1-120); CH1 region (amino acids: 121-218); upperhinge region (amino acids 219-221), and caspase III cleavage site(222-226):

(SEQ ID NO: 2) QVQLVESGGG VVQPGRSLRL SCAASGFTFS RFAMHWVRQAPGKGLEWVAV ISYDGGNKYY AESVKGRFTI SRDNSKNTLYLQMNSLRAED TALFYCARGY DVLTGYPDYW GQGTLVTVSSASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVSWNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSNFGTQT YTCNVDHKPS NTKVDKTVER KGDEVDAmino acid sequence for light chain of 29G4v9 Fab (comprised of VLregion (amino acids: 1-108) and CL region (amino acids: 109-214):

(SEQ ID NO: 3) DIQLTQSPSF LSASVGDRVT ITCRASQSIG RSLHWYQQKPGKAPKLLIKY ASQSLSGVPS RFSGSGSGTE FTLTISSLQPEDFATYYCHQ SSRLPFTFGP GTKVDIKRTV AAPSVFIFPPSDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGECAmino acid sequence of the human PAC1 ECD construct:

(SEQ ID NO: 4) GSMAHSDGIF KKEQAMCLEK IQRANELMGF NDSSPGCPGMWDNITCWKPA HVGEMVLVSC PELFRIFNPD QDMGVVSRNC TEDGWSEPFP HYFDACGFDE YESET

Purified human PAC1 ECD and the anti-PAC1 Fab were initiallyco-crystallized using sitting drop vapor diffusion method withcommercially available screens. The crystallized condition (Qiagen MPDSuite Screen #61 (134561)) was further expanded using hanging drop vapordiffusion method. Protein and crystallization buffer (0.1M Citric AcidpH 4.0, 40% MPD) were mixed 1:1 in 1 μl hanging drops over a reservoirsolution of crystallization buffer at 4° C. Rod-shaped crystals formedwithin several weeks.

The crystal was equilibrated in the crystallization buffer ascryo-protectant, and was frozen in liquid nitrogen for shipment toLawrence Berkeley National Laboratories for data collection. The dataset was collected at the Advanced Light Source Synchrotron Beamline5.0.2 on an ADSC-Q315r CCD Detector (λ=1.000 Å). The data wereintegrated and scaled using HKL2000 (Otwinowski and Minor, MethodsEnzymology, Vol. 276, 307-326, 1997) and were 99.8% complete to 2.00 Åwith R_(merge) of 0.081 (98.0% complete last shell 2.07-2.00 Å withI/σ=2.35). The crystals belong to the orthorhombic space group P2₁2₁2with unit cell dimensions of a=65.2 Å, b=177.9 Å, c=53.8 Å, α=90°,β=90°, γ=90°. The crystal structure was solved by molecular replacementusing PhaserMR (Winn et al., Acta Crystallogr., Sect. D: Biol.Crystallogr., Vol. 67: 235-242, 2011). A proprietary Fab structure wasused as the first search model to solve the anti-PAC1 Fab component.Subsequent molecular replacement used PDBID: 2JOD (Sun et al., Proc.Natl. Acad. Sci. USA, Vol. 104: 7875, 2007), a human PAC1 ECD NMRstructure, as starting model to solve the human PAC1 ECD component.There is one ECD molecule and one Fab molecule in the asymmetric unit.The structure was refined using both Refmac5 (Winn et al., ActaCrystallogr., Sect. D: Biol. Crystallogr., Vol. 67: 235-242, 2011;Murshudov et al., Acta Crystallogr., Sect. D: Biol. Crystallogr., Vol.67: 355-367, 2011) and Phenix.refine (Adams et al., Acta Crystallogr.,Sect. D: Biol. Crystallogr., Vol. 66: 213-221, 2010), and model buildingwas performed using the graphics program Coot (Emsley and Cowtan, ActaCrystallogr., Sect. D: Biol. Crystallogr., Vol. 2004, 60: 2126-2132,2004).

The structure of the human PAC1 ECD: anti-PAC1 Fab complex was refinedto 2.00 Å with an R-factor of 20% and Rfree of 23%. A front view andside view of the structure of the complex is shown in FIGS. 1A and 1B,respectively. The interaction between the 29G4v9 Fab and the PAC1 ECD iscomprised of hydrophobic, electrostatic and hydrogen bond interactions.The interaction between the 29G4v9 Fab and the PAC1 ECD has buriedsurface area (1613 Å²) and shape complementarity (0.695) values that aretypical for antibody-antigen interactions. All amino acids in the PAC1ECD that contained at least one non-hydrogen atom at a distance of 5 Åor less from a non-hydrogen atom in the 29G4v9 Fab were determined to bethe core interface amino acids in the PAC1 ECD. Distances of the atomswere calculated with the PyMOL program (DeLano, W. L. The PyMOLMolecular Graphics System. (Palo Alto, 2002)). The core interface aminoacids in the PAC1 ECD include Asp59, Asn60, Ile61, Arg116, Asn117,Thr119, Asp121, Gly122, Trp123, Ser124, Glu125, Pro126, Phe127, Pro128,His129, Tyr130, Phe131, Asp132, and Gly135 with the amino acid positionnumbers relative to SEQ ID NO: 1.

The interface between the 29G4v9 Fab and the PAC1 ECD in the crystalstructure was analyzed to identify regions where the interactionsbetween the two molecules were sub-optimal. Based on the structuralanalysis, mutations of the amino acids in the light and heavy chainvariable regions were designed to enhance the interaction in theseregions between the Fab and the PAC1 ECD to improve binding affinityand/or inhibitory potency of the antibody. In particular, analysis ofthe interaction between the Fab light chain and PAC1 ECD revealed fourregions where mutations in the Fab light chain may possibly improveinteractions with PAC1. In zone 1, a region containing PAC1 ECD aminoacids Glu120 and Asp121, mutation of Gln27 in the light chain CDR1 (SEQID NO: 3) to lysine, tyrosine, or arginine was proposed to providebetter charge complementarity or hydrogen bonding potential with theGlu120 and Asp121 PAC1 amino acids (FIG. 2A). Zone 2 is a region withpositive electrostatic potential and mutation of Ser28 in the lightchain CDR1 (SEQ ID NO: 3) to glutamate was proposed to provide bettercharge complementarity (FIG. 2A). Zone 3 is a hydrophobic regioncontaining PAC1 ECD Phe127 residue and has hydrogen bonding potential.Gly30, Arg31, and Ser32 in the light chain CDR1 lie somewhat distantfrom zone 3 (FIG. 2A). Thus, multiple mutations were proposed at thesethree sites as summarized in Table 6 below to improve the hydrophobic orhydrogen bonding interactions between these three residues and this zoneof the PAC1 ECD. Arg93 in the light chain CDR3 sits in a pocket of PAC1residues with negative electrostatic potential (zone 4; FIG. 2B).However, due to the geometry, Arg93 does not form any direct hydrogenbonds with PAC1 residues. Mutations of Arg93 in the light chain CDR3 toglutamine, lysine, histidine, or asparagine were proposed to providealternate charge complementarity or hydrogen bond potential withresidues in the PAC1 ECD (FIG. 2B).

Analysis of the interaction between the 29G4v9 Fab heavy chain and PAC1ECD revealed three main regions where mutations in the Fab heavy chainmay improve interactions with the PAC1 ECD. As shown in FIG. 3A, zone 5encompasses PAC1 amino acid Phe131, and can be divided into twosub-zones that lie on either side of Phe131. Arg31 and Phe32 in theheavy chain CDR1 lie in these sub-zones and mutations at these siteswere proposed to improve the hydrophobic interactions with PAC1 Phe131residue or provide alternate charge complementarity interactions. SeeTable 6 for list of mutations. In zone 6, which includes PAC1 ECDresidues Asn60 and Ile61 (relative to SEQ ID NO: 1), mutation of heavychain CDR2 residues Tyr53, Asp54 and Gly56 were proposed to improvehydrophobic interactions or provide alternate hydrogen bonding withAsn60 and Ile61 PAC1 residues (FIG. 3B). In zone 7, a region withhydrophobic residues and some negative electrostatic potential,mutations of heavy chain CDR3 residues Val102, Leu103 and Thr104 as setforth in Table 6 were proposed to improve hydrophobic interactions orprovide alternate hydrogen bonding interactions (FIG. 3C).

A summary of the specific mutations proposed to improve the interactionbetween the anti-PAC1 antibody and the human PAC1 receptor based on theanalysis of the crystal structure of the Fab/PAC1 ECD complex isprovided in Table 6 below.

TABLE 6 Summary of Structure-Based Mutations in PAC1 Antibody VariableRegions Amino Acid Position¹ Mutations Light Chain Gln27 Lys, Tyr, ArgSer28 Glu Gly30 Leu, Val, Ile, Thr, Tyr, Phe, Met, Ala, His, Asn, Gln,Glu, Asp, Trp, Ser Arg31 Phe, Tyr, Leu, Ser, Thr, Gln, Asn Ser32 Leu,Thr, Ala, Met, Lys, Gln Arg93 Gln, Lys, His, Asn Heavy Chain Arg31 Leu,Tyr, Met, Ile, Lys Phe32 Tyr, Lys, Gln Tyr53 Gln, Leu, Ser Asp54 Tyr,Gln, Asn Gly56 Ser, Thr Val102 Phe, Tyr, Trp, Leu, Thr, Ile, Met Leu103Asn, Gln, Phe, Met, Ser, Thr Thr104 Ser ¹Amino acid positions for thelight chain are relative to SEQ ID NO: 3 and amino acid positions forthe heavy chain are relative to SEQ ID NO: 2.

In addition to the mutations designed by analysis of the interactingamino acids between the anti-PAC1 Fab and the human PAC1 ECD asdescribed above, an in silico affinity maturation analysis using thecrystal structure was also conducted to identify additional mutations toimprove the binding affinity and/or inhibitory potency of the anti-PAC1antibody. Amino acid residues in the 29G4v9 Fab involved in binding tothe human PAC1 ECD were identified by visual inspection of the crystalstructure of the complex described above. These interface residues ofthe antibody were selected for virtual mutation to all other amino acidsexcept for cysteine. The impact of the mutation to the antibody/PAC1 ECDbinding interaction was assessed by calculating the change in bindingfree energy (ΔΔG_(binding)) upon mutation of a particular residue usingDiscovery Studio molecular modeling software from Biovia. A negativevalue of ΔΔGbinding indicates that the mutation results in a strongerbinding to the PAC1 ECD compared the parental molecule. Thesecalculations identified approximately 65 mutations that led to negativevalue of ΔΔGbinding. These 65 mutations were further narrowed down to 50(18 in the light chain and 32 in the heavy chain) based on the visualinspection and analysis of the “modeled” structure of these variantswith the PAC1 ECD. These 50 mutations predicted to increase the bindingaffinity of the antibody for PAC1 based on the binding free energycalculations are summarized in Table 7 below.

TABLE 7 Summary of Mutations in PAC1 Antibody Variable Regions Predictedfrom In Silico Analysis Amino Acid Position¹ Mutations Light Chain Gln27Lys, Tyr, Arg Gly30 Arg Ser32 Arg, Asn, His, Leu, Val Ser91 Lys, ThrSer92 Gln, Ile Leu94 Arg, His, Tyr Phe96 Arg, Lys Heavy Chain Phe32 HisAla33 Ser Ser52 Ile, Gln, Met Asp54 Tyr, Gln, Asn, Ile, Leu Gly55 AlaGly56 Arg, Asn, His, Tyr Asn57 Arg, His, Lys, Tyr Lys58 Glu Glu62 ArgGly99 Ala Tyr100 His Val102 Ile Leu103 Arg Thr104 Ser, His Gly105 Ser,Lys Tyr106 Arg, Lys Asp108 Arg ¹Amino acid positions for the light chainare relative to SEQ ID NO: 3 and amino acid positions for the heavychain are relative to SEQ ID NO: 2.

The in silico approach resulted in the identification of additionalmutations, both in terms of different amino acids as well as differentpositions within the light and/or heavy chain, as compared with thestructure-based analysis.

The mutations described in this example were incorporated into ananti-PAC1 antibody by recombinant production and tested for the abilityto inhibit PACAP-induced activation of human PAC1 in an in vitrocell-based assay as described in Example 3 herein.

Example 2. Yeast Display Affinity Maturation of 29G4v10 Human PAC1Antibody

One powerful approach for affinity maturation involves constructingyeast-displayed libraries of antibody Fab mutants and selecting forimproved binders through fluorescence-assisted cell sorting (FACS)(FIG.4). To generate anti-PAC1 antibodies with improved inhibitory potency,the 29G4v10 antibody (VH region of SEQ ID NO: 191; VL region of SEQ IDNO: 52) was affinity matured by FACS of yeast-displayed Fab libraries.The library designs were guided by the solved co-crystal structuredescribed in Example 1 of the complex between human PAC1 ECD and 29G4v9Fab, the CDRs of which are nearly identical to those of 29G4v10.Structural analysis initially identified six and seven CDR positionswithin the light chain (LC) and heavy chain (HC) for mutagenesis,respectively, and suggested strategies for affinity enhancement. Pointmutants were designed to improve hydrophobic interactions and chargecomplementarity, and to provide alternate hydrogen-bond interactionsacross the interface. See Example 1. These point mutants initiated anengineering approach that involved iterative rounds of production,characterization, and rational combination of beneficial mutations. Theyeast library designs sought to complement the linear approach describedin Example 1 by more comprehensively exploring mutation combinationsamong the 13 positions and augmenting the diversification strategy ateach chosen position.

By making separate LC and HC libraries, the theoretical diversities werekept to a manageable size of <10⁷. The LC library was designed toutilize MIX19 saturation mutagenesis at five of the six chosen positions(Gln27, Gly30, Arg31, Ser32, and Arg93 of SEQ ID NO: 52). MIX19represents a trimer phosphoramidite (codon) mixture encoding all aminoacids except for cysteine. At the remaining light chain position (Ser28of SEQ ID NO: 52), mutation to serine, glutamate, alanine or a stopcodon was employed. To explore all seven HC positions (Arg31, Phe32,Tyr53, Gly56, Val102, Leu103, and Thr104 of SEQ ID NO: 191) in onelibrary, we designed a custom mixture of nine codons (MIX9) fordiversification at five of the seven heavy chain CDR positions (Arg31,Phe32, Tyr53, Val102, and Leu103 of SEQ ID NO: 191). Custom MIX9comprised hydrophobic amino acids, basic amino acids, and hydrogen bonddonors and acceptors (e.g. F, L, Y, M, Q, H, K, R, and S). Importantly,the custom MIX9 excluded cysteine, asparagine, and tryptophan tominimize introduction of sequence liabilities that could pose downstreammanufacturability risks. Mutation to glycine, alanine, serine, andthreonine was performed for the remaining two heavy chain positions(Gly56 and Thr104 of SEQ ID NO: 191). In summary, for this firstcampaign a mutHC library with a theoretical diversity of 8.5×10⁶ and amutLC library with a theoretical diversity of 9.9×10⁶ were designed, andthe constructed libraries oversampled the theoretical diversities by>9-fold.

The two constructed mutHC and mutLC Fab libraries were enriched forbinding to the human PAC1 ECD using FACS, increasing the stringency witheach successive round by lowering the concentration of ECD used forbinding (Round 1: 30 nM PAC1 ECD; Round 2: 0.67 nM PAC1 ECD; and Round3: 0.2 nM PAC1 ECD). An identically treated 29G4v10 Fab-yeast sample wasroutinely used to gate specifically for yeast clones exhibiting improvedbinding relative to the parental Fab. A normalized binding/display ratiofor each clone was calculated by dividing the median fluorescencebinding signal for each clone by the median fluorescence display signalfor each clone. By round 3, improved binders were enriched from themutHC library, but not the mutLC library. An abbreviated screen of ˜200yeast clones from the mutHC Round 3 pool yielded 11 modestly improvedbinders (Table 8). The improved affinity variants were producedrecombinantly and evaluated for in vitro functional activity asdescribed in Example 3. Fortuitously, the aspartate isomerization sitewithin the 29G4v10 parental Fab, a potential liability formanufacturability, was remediated in all of these 11 unique mutants.

TABLE 8 Top Improved Binders from MutHC Library Screen Substitutionswith respect to 29G4v10 Yeast Binding Screen VII sequence (SEQ Data at0.2 nM PAC1 ID NO: 191)¹ Normalized Binding Variant HC HC HCSignal/Display Signal Mutant vs. Wild- Ab ID CDR1 CDR2 CDR3 (B/D) TypeB/D Ratio iPS:421855 R31K; Y53F; V102L 0.40 1.86 F32Y D54K; G56SiPS:421861 F32Y D54Q V102L 0.38 1.80 iPS:421867 R31H Y53F; V102M 0.351.61 D54S; G56S iPS:421873 R31K D54R V102L 0.42 1.95 iPS:421879 F32YD54S; V102L; 0.33 1.56 G56A T104S iPS:421885 R31H; Y53F; V102L 0.45 2.09F32Y D54K; G56A iPS:421891 R31H; D54R; V102L 0.49 2.27 F32Y G56AiPS:421897 R31H; Y53F; V102F 0.39 1.83 F32Y D54Y; G56S iPS:421903 R31HY53F; V102F 0.44 2.07 D54F iPS:421909 R31H; Y53F; V102F 0.43 2.01 F32YD54M; G56T iPS:421915 R31Y Y53H; V102L; 0.35 1.63 D54R; T104S G56T29G4v10 — — — 0.21 1.00 Wild-Type ¹There were no changes in the sequenceof the light chain relative to the 29G4v10 antibody for any of thesevariants.

To generate further affinity improvements, a chain-shuffled library thatcombined enriched mutations from the mutHC and mutLC sorted pools wasalso constructed. To improve discrimination among the top bindingclones, a binding off-rate driven selection and screening strategy wasimplemented (FIG. 5). Yeast cells displaying the mutant Fabs were firstsaturated with biotinylated human PAC1 ECD and washed extensively beforea prolonged incubation in buffer containing a large excess of unlabeledhuman PAC1 ECD (up to 24 hours). The incubation with unlabeled humanPAC1 ECD, which occurred at temperatures ranging from 25° C. to 37° C.,rendered dissociation events from the cells irreversible. Cellsretaining the most binding to biotinylated PAC1, thereby exhibiting theslowest off-rate, were isolated by FACS after staining with afluorescent streptavidin conjugate (FIG. 5). Yeast clones displayingFabs exhibiting the slowest off-rates were the most highly fluorescent.

In the off-rate driven sort of the chain-shuffled library, anidentically treated 29G4v10 Fab-yeast sample was employed tospecifically isolate cells with greater biotinylated PAC1 binding afterovernight competition with unlabeled PAC1. From two pools collectedunder different gating stringencies, ˜600 individual yeast clones werescreened using the binding off-rate assay and over 190 clones withhigher remaining PAC1 binding than the parental 29G4v10 Fab wereidentified. Specificity of binding of these promising clones wasevaluated by confirming there was no binding of the clones to the ECDsof unrelated receptors (programmed cell death protein 1 (PD1) andgastric inhibitory polypeptide receptor (GIPR)). Mutants containingadditional cysteine anomalies, N-linked glycosylation, aspartateisomerization, asparagine deamidation, and tryptophan oxidation sitesrelative to the starting 29G4v10 sequence were also removed during thescreen. The top 30 binding mutants are shown in Table 9 with sequencechanges in the CDRs from parental 29G4v10 antibody and the percentage ofhuman PAC1 ECD binding following the off-rate assay. Higher percentageassociation of PAC1 ECD binding indicates that the mutant Fabs have aslower off-rate.

TABLE 9 Top Improved Binders from Off-Rate Driven Screen ofChain-Shuffled Library Secondary Screen: off-rate competition at 30° C.Normalized Substitutions with Substitutions with PAC1 ECD respect to29G4v10 respect to 29G4v10 binding VH sequence VL sequence % remaining(SEQ ID NO: 191) (SEQ ID NO: 52) association (mutant vs. Clone HC HC HCLC LC LC after Q27K LC ID CDR1 CDR2 CDR3 CDR1 CDR2 CDR3 off-ratevariant) 2_C11 R31Y; D54S; V102L Q27K; — — 77% 3.42 F32Y G56S R31Q 1_D07R31F; Y53S; V102L Q27K; — — 56% 2.66 F32Y D54F; R31Q G56S 2_B10 R31H;D54Q; V102L Q27R; — R93F 54% 2.79 F32Y G56S R31L; S32A 2_G07 R31Y; Y53H;V102P Q27K; — — 57% 2.41 F32Y D54Y; R31Q G56T 1_H04 R31Y Y53H; V102LQ27K; — — 52% 2.37 D54S; T104S R31Q G56A 1_F03 — — — Q27K; — — 47% 3.23R31W 2_E08 — — — Q27K; — R93M 50% 2.29 R31W 1_F01 R31H D54S V102L Q27R;— R93M 50% 2.21 R31L; S32A 2_F10 R31H; D54S V102L; Q27K — — 46% 2.54F32Y T104S G30W; R31K 1_B08 R31Y; Y53S; V102L Q27K; — R93M 50% 2.18 F32YD54R; S28E; G56S G30M; R31S; S32L; L33H; ΔH34¹ 1_A11 — — — Q27R; — R93Y43% 2.48 S28A; G30S; R31N; S32L; L33H; ΔH34¹ 2_A10 R31Y; Y53S; — Q27K; —R93M 55% 1.70 F32Y D54M; S28A; G56T G30W; R31H; S32N 2_G10 R31M; D54S;V102L Q27K; — R93M 49% 2.07 F32Y G56S R31Q 2_E10 R31K; D54M; V102L Q27K;— — 68% 1.53 F32Y G56A R31W 2_C05 R31Y; Y53S; V102L Q27K; — R93M 48%1.90 F32Y D54R; R31Q G56S 1_A09 R31K; D54S; V102L Q27K; — — 36% 2.38F32Y G56A R31Q 2_C02 R31K; Y53F; V102L Q27K; — R93M 41% 2.14 F32Y D54S;L103M R31W G56S 1_H06 F32Y D54S; V102L; Q27K; — R93F 38% 2.16 G56A T104SS28A; R31F 2_D01 — — V102L Q27K; — R93L 34% 2.10 R31W 2_B11 R31Y; Y53H;V102L; Q27R; — R93M 45% 1.53 F32Y D54S T104S R31M 2_F05 R31H; D54SV102L; Q27R; — R93I 51% 1.54 F32Y T104S S28A; G30F; R31G; S32N 1_F10R31Y Y53H; V102L; Q27K; — R93M 39% 1.96 D54S; T104S S28A; G56A G30W;R31H; S32N 1_D05 R31Y; Y53S; V102L Q27H; — — 45% 1.82 F32Y D54R; S28A;G56S G30Y; R31H; S32N 1_E01 R31F Y53S; V102L; Q27K; — — 50% 1.39 D54H;L103M; R31W G56T T104S 2_H10 — — — Q27R; — R39M 53% 1.09 S28A; G30F;R31G; S32N 2_B08 — D54S; V102L Q27K; — R93M 43% 1.91 G56S S28A; G30W;R31H; S32N 1_A10 F32Y Y53F; V102L Q27K; — R93L 49% 1.65 D54Q; R31W G56S1_B11 R31M Y53H; V102L Q27K; — — 44% 1.65 D54R; R31Q G56T 1_D04 R31H;D54R; V102L Q27K; — — 37% 2.12 F32Y G56A R31Q 1_C09 R31H; Y53F; — Q27K;— — 39% 1.80 F32Y D54H R31Q 29G4v10 — — — — — — 25% 0.70 Wild- Type VL —— — Q27K — — 22% 1.00 Q27K variant ¹The histidine residue at position 34relative to the 29G4v10 light chain variable region sequence (SEQ ID NO:52) is deleted in these mutants.

A set of second-generation libraries was designed to generate furtheraffinity improvements. The first generation libraries described abovefocused diversification at a subset of the 29G4v10 parental antibody CDRpositions that were within 4.5 Å of the PAC1 ECD in the crystalstructure (Example 1). For the second generation libraries, mutagenesisin regions that were largely untouched in the first generationlibraries, such as CDR2 and CDR3 of the light chain, were explored. Forseveral positions already explored in the first generation libraries,sequencing trends were used to diversify to the limited set ofneutral/beneficial mutations that had emerged after three rounds ofsorting. Finally, some buried framework residues that could influenceCDR conformations were targeted for limited diversification, with themutation strategy favoring amino acids frequently found at the sameposition in other human VH3 and VK3 germlines.

In total, four second generation Fab libraries were designed to target24 heavy chain CDR residues (amino acids 27, 29, 31-34, 49, 52-57, 70,72, 77, 79, 98, 100-104, and 106 of SEQ ID NO: 191) and 17 light chainCDR residues (amino acids 27, 28, 30-32, 34, 46, 49-54, 92-94, and 96 ofSEQ ID NO: 52) for diversification. The restricted diversity at manytargeted positions enabled interrogation of more CDR positions withinone library and co-optimization of HCDR1 with HCDR3 and LCDR1 withLCDR3. The four libraries that were constructed provided 8-24× coverageof the theoretical diversities ranging from 7×10⁶ to 1×10⁷.

The four constructed Fab libraries were enriched for binding to thehuman PAC1 ECD using FACS, as described above. By Round 3, only themutHCDR2 and mutLCDR1-LCDR3 libraries yielded pools with equivalent orsuperior binding to parental 29G4v10 antibody. Therefore, these twopools were carried forward to make a mutH2/mutL1L3 chain-shuffledlibrary for further affinity improvements. To enrich for the highestaffinity mutants, 2B10, a top-performing yeast clone from the firstgeneration libraries (Table 9), was used to set more stringent sortgates. Following an overnight off-rate competition with unlabeled PAC1at 30° C. or 37° C., the yeast clones with significantly reducedoff-rates compared to the 2B10 clone could be sorted out. A limitedscreen of ˜200 clones revealed that ˜100 had slower off-rates than 2B10,but most of the promising binders contained a potential asparaginedeamidation liability within HCDR2. Non-specific binding to the ECDs ofPD1 or GIPR was minimal for all clones screened. Applying stringentbinding and sequence filters yielded ten top mutants with significantlyimproved PAC1 binding than the 2B10 clone (>2× higher percentassociation after 37° C. overnight competition) and without anypotential sequence liabilities (Table 10). Sequence changes fromparental 29G4v10 antibody for these top ten mutants and the percentageof human PAC1 ECD binding following the off-rate assay at 30° C. and 37°C. are shown in Table 10. Percentage association was calculated as thenormalized binding after off rate assay divided by the normalizedbinding without the off rate assay. Higher percentage association ofPAC1 ECD binding indicates that the mutant Fabs have a slower off-rate.

TABLE 10 Top Improved Binders from Off-Rate Screen of Second GenerationChain- Shuffled Library Substitutions with Substitutions with % respectto 29G4v10 respect to 29G4v10 association VH sequence VL sequence after(SEQ ID NO: 191) (SEQ ID NO: 52) off-rate Clone HC HC HC HC HC LC LC LCscreen ID CDR1 FR2 CDR2 FR3 CDR3 CDR1 CDR2 CDR3 30° C. 37° C. 30_H10 — —D54S; I70V — Q27K; — — 75.8% 63.6% G56A; R31W N57F 30_D05 — A49G S52N;I70V — Q27K; — — 74.2% 57.9% D54R; R31W G56H; N57G 30_F08 — A49G S52T; —— Q27K; — — 67.1% 54.6% D54T; S28A; N57A R31W 30_A05 — A49G S52N; — —Q27K; — — 65.8% 50.5% D54F; R31W G56D; N57A 30_E08 — A49G S52N; — —Q27K; — — 60.9% 46.5% Y53F; R31W D54Q; G56T; N57T 37_E09 — A49G D54S;I70V — Q27K; — — 73.4% 49.2% G56D; R31W N57L 37_F04 — A49G Y53F; I70L —Q27K; — — 73.0% 46.5% D54S; R31W N57S 37_B06 — A49G D54S; I70M — Q27K; —— 68.6% 43.0% G56A; R31W N57S 37_H05 — A49G D54T; I70M — Q27K; — — 64.3%40.2% G56A; R31W N57Q 37_A11 — A49G D54T; I70V — Q27K; — — 64.9% 36.6%G56Q; R31Y N57F 2_B10 R31H; — D54Q; — V102L Q27R; — R93F 53.0% 21.5%Control F32Y G56S R31L; S32A 29G4v10 — — — — — — — — 10.4%  8.5% Wild-Type

As shown in Table 10, all of these top ten binding mutants contained aQ27K mutation in CDRL1 and all but one contained a R31W mutation inCDRL1. All the mutants had mutations at amino acid positions D54 and N57in CDRH2 and most also had a mutation at amino acid position G56 inCDRH2. Conservative mutations at amino acid positions 49 and 70 in theheavy chain framework 2 (FR2) and framework 3 (FR3) regions,respectively, were also observed in many of these ten mutants.

In summary, guided by the structure of the PAC1 ECD in complex with the29G4v9 Fab, a closely related variant of 29G4v22 and 29G4v10 anti-PAC1neutralizing antibodies, combinatorial libraries of 29G4v10 mutants weredesigned and sorted for improved binding to the PAC1 ECD. To isolate themost improved binders, enriched mutations were combined throughconstruction of CDR-shuffled and/or chain-shuffled libraries forselection under more stringent conditions. Screens of individual yeastFab clones after sorting yielded improved binders to human PAC1 ECD withsignificantly slower binding off-rates as compared to the 29G4v10parental antibody and minimal non-specific binding. A subset of theimproved affinity variants were produced recombinantly and evaluated forin vitro functional activity as described in Example 3.

Example 3. In Vitro Functional Activity of Human PAC1 Antibody Variants

To evaluate the effect of the mutations in the heavy and light chainvariable regions identified by the analysis of the co-crystal structure(Example 1) or the yeast display libraries (Example 2) on the inhibitorypotency of the anti-PAC1 antibody, the variants were produced byrecombinant expression methods as complete bivalent monoclonalantibodies and/or as monovalent Fab-Fc fusions (e.g. Fab region fused todimeric IgG Fc region) and evaluated in a cell-based cAMP assay asdescribed in more detail below. The light chains of the monoclonalantibodies and Fab fragments comprised the light chain variable regionfrom the indicated antibody variant fused to a human kappa light chainconstant region having the sequence of SEQ ID NO: 318 or SEQ ID NO: 319.The heavy chains of the monoclonal antibodies and Fab-Fc fusionscomprised the heavy chain variable region from the indicated antibodyvariant fused to an aglycosylated, disulfide-stabilized human IgG1zconstant region having the sequence of SEQ ID NO: 325.

PAC1 antibody variant sequences were generated by site directedmutagenesis (SDM) or by Golden Gate Assembly (GGA) in those cases whereSDM was unsuccessful. Site directed mutagenesis utilized pairedmutagenic primers that flanked the mutation site. Whole vector PCRreactions were carried out using double stranded plasmid DNA templates.The primers for all of the desired mutations in a particular clone werecombined into a master primer mix, with one to several mutations beingincorporated in an individual reaction. Following amplification, thetemplate plasmid DNA was removed by digestion with DpnI, an endonucleasewhich preferentially cleaves methylated DNA. The SDM product was thentransformed into competent cells for growth and screening by sequencing.The SDM reactions were performed using the QuikChange Lightning MultiSite-Directed Mutagenesis Kit (Agilent) following the manufacturer'sdirections.

Where SDM was unsuccessful, an alternative cloning strategy wasutilized. Briefly, GGA relied upon Type II restriction enzymes and T4DNA ligase to cut and seamlessly ligate together multiple DNA fragments.(Engler et al., PLOS One, Vol. 3(11): e3647, 2008). In this example, themultiple DNA fragments consisted of (i) a synthetic nucleic acidsequence (gBlock, Integrated DNA Technologies, Coralville, Iowa)encoding a Kozak consensus sequence, a signal peptide sequence and anantibody variable region sequence; (ii) an antibody constant domainfragment released from a Parts vector; and (iii) the expression vectorbackbone. The GGA reactions were composed of 10 ng of gBlock, 10 ng ofthe Part vector, 10 ng of the expression vector, 1 μl 10× Fast DigestReaction Buffer+0.5 mM ATP (Thermo Fisher, Waltham, Mass.), 0.5 μlFastDigest Esp3I (Thermo Fisher, Waltham, Mass.), 1 μl T4 DNA Ligase (5U/μl, Thermo Fisher, Waltham, Mass.) and water to 10 μl. The reactionswere performed over 15 cycles consisting of a 2 minute digestion step at37° C. and a 3 minute ligation step at 16° C. The 15 cycles werefollowed by a final 5 minute 37° C. digestion step and a 5 minute enzymeinactivation step at 80° C.

Following cloning, PAC1 antibody polypeptides of which the first 22amino acids were the VK1 signal peptide (MDMRVPAQLLGLLLLWLRGARC; SEQ IDNO: 486) were generated by transiently transfecting 293 HEK cells withthe corresponding cDNAs. Cells at 1.5×10⁶ cells/ml were transfected with0.5 mg/L DNA (0.5 mg/L PAC1 in the pTT5 vector) or (0.1 mg/L PAC1 inpTT5 vector with 0.4 mg/L empty pTT5 vector) (Durocher et al., NRCC,Nucleic Acids. Res., Vol. 30: e9, 2002) with 4 ml PEI/mg DNA in F17media (Thermo Fisher). Yeastolate and Glucose were added to cultures 1hour after transfection, and cells were then grown in suspension usingF17 expression medium supplemented with 0.1% Kolliphor, 6 mM L-Glutamineand 50 μg/ml Geneticin for 6 days after which the conditioned media washarvested for purification.

The PAC1 antibody variants were purified from the conditioned mediausing protein A affinity chromatography (Mab Select SuRe, GE HealthcareLife Sciences, Little Chalfont, Buckinghamshire, UK) followed by cationexchange chromatography (SP Sepharose High Performance columns (SP HP)(GE Healthcare Life Sciences). The protein concentration of eachpurified pool was determined by UV absorbance at 280 nm (A280) using aNanoDrop 2000 (Thermo Fisher Scientific, Rockford, Ill., USA). Thepurified pools were dialyzed against 2 L of 10 mM sodium-acetate, 9%sucrose, pH 5.2 (A52Su) using 20 kDa MWCO Slide-A-Lyzer dialysis flasks(Thermo Fisher Scientific) for 2 hours at 4° C. with gentle stirring ona stir plate. The used dialysate was decanted away, a fresh 2 L of A52Suwas added and dialysis proceeded overnight. After dialysis, the sampleswere concentrated using 30 kDa MWCO ultrafiltration concentrators(Thermo Fisher Scientific) centrifuged at 2,000×g in a swinging-bucketrotor until each sample was approximately 40 mg/mL based on A280. Thefinal products were analyzed for main peak purity using Caliper LabChipGXII microcapillary electrophoresis (PerkinElmer, Waltham, Mass., USA)and size exclusion chromatography using an ACQUITY UPLC Protein BEH SECcolumn, 200 Å, 4.6×300 mm (Waters Corporation, Milford, Mass., USA). Theendotoxin content was measured using an Endosafe-MCS (Charles River,Wilmington, Mass., USA) and 0.05 EU/mL PTS cartridges (Charles River).

The functional activity of the purified monoclonal antibodies or Fab-Fcfusion proteins was assessed using a cell-based PAC1 receptor cAMPactivity assay. Both PACAP38 and PACAP27 are agonists of the PAC1receptor, activation of which results in an increase in intracellularcAMP. The assay employed a human neuroblastoma-derived cell line(SH-SY5Y; Biedler J L et al., Cancer Res., Vol. 38: 3751-3757, 1978)obtained from ATCC (ATCC Number CRL-2266; “CRL-2266 cells”). CRL-2266cells express human PAC1 receptor endogenously (Monaghan et al., JNeurochem., Vol. 104(1): 74-88, 2008). In addition, a CHO cell linestably expressing the rat PAC1 receptor (GenBank Accession No.NM_133511.2) or the cynomolgus monkey PAC1 receptor (NCBI ReferenceSequence XP_015303041.1) was used in place of the CRL2266 cells forassays to evaluate the species cross-reactivity of the anti-PAC1antibodies or Fab-Fc fusions at the rat and cynomolgus monkey PAC1receptors. The LANCE Ultra cAMP assay kit (PerkinElmer, Boston, Mass.)was used to measure cAMP concentration.

On the day of the assay, the frozen CRL-2266 cells were thawed at 37° C.and were washed once with assay buffer. 10 μL of cell suspensioncontaining 2,000 cells was added into 96 half-area white plates. Afteradding 5 μL of the anti-PAC1 variant monoclonal antibody or Fab-Fcfusion protein (10 point dose response curve: concentration range from 1μM to 0.5 fM), the mixture was incubated for 30 min at room temperature.Then, 5 μL of human PACAP38 (10 pM final concentration) was added as anagonist and the mixture was further incubated for 15 min at roomtemperature. After human PACAP38 stimulation, 20 μL of detection mix wasadded and incubated for 45 minutes at room temperature. The plates wereread on EnVision instrument (PerkinElmer, Boston, Mass.) at emissionwavelength 665 nm. Data were processed and analyzed by Prizm (GraphPadSoftware Inc.) to show POC (percent of control, in which control isdefined as the activity of the agonist used in the assay) as a functionof the tested antagonist concentration (e.g. anti-PAC1 variant antibodyor Fab-Fc fusion protein), and were fitted with standard nonlinearregression curves to yield IC50 values. POC was calculated as follows:

${POC} = {100 \times {Em}\; 665\mspace{14mu}{of}\mspace{14mu}\frac{\begin{matrix}{{{Agonist}\mspace{14mu}{response}\mspace{14mu}{with}\mspace{14mu}{antagonist}} -} \\{{cell}\mspace{14mu}{response}\mspace{14mu}{without}\mspace{14mu}{agonist}\mspace{14mu}{and}\mspace{14mu}{antagonist}}\end{matrix}}{\begin{matrix}{{{Agonist}\mspace{14mu}{response}\mspace{14mu}{without}\mspace{14mu}{antagonist}} -} \\{{cell}\mspace{14mu}{response}\mspace{14mu}{without}\mspace{14mu}{agonist}\mspace{14mu}{and}\mspace{14mu}{antagonist}}\end{matrix}}}$

Monovalent Fab-Fc fusion proteins were generated with the mutationssummarized in Tables 6 and 7 and tested for functional activity in thecell-based cAMP assay described above. The mutant Fab-Fc fusion proteinswere segregated into two separate groups: mutations that improveinhibitory potency against the human PAC1 receptor compared to theparent molecule and mutations characterized as neutral (Table 11).Mutations were characterized as neutral if the mutation had an averagepotency less than 1.5× weaker than that of parent molecule, and at leastone potency measurement tighter than parent molecule in same run.

TABLE 11 In vitro inhibitory potency of single mutant Fab-Fc fusionproteins Fab-Fc Fusion Protein ID No. Mutations¹ IC50 (nM) ImprovedPotency Mutations 29G4v10 Fab-Fc fusion parent — 10.37 molecule PL-45360LC Q27K 4.52 PL-45362 LC Q27R 6.32 PL-45398 HC D54N 1.78 PL-45399 HCD54I 2.48 PL-45400 HC D54L 3.11 PL-45405 HC D54Q 3.46 PL-45397 HC D54Y3.62 PL-45406 HC G56R 2.81 PL-45407 HC G56N 7.98 PL-45408 HC G56H 9.46PL-45402 HC G56S 9.49 PL-45415 HC E62R 4.27 PL-45418 HC V102I 9.68Neutral Mutations 29G4v10 Fab-Fc fusion parent — 10.37 molecule PL-45370LC S91T 15.19 PL-45377 LC L94R 11.05 PL-45386 HC R31K 12.12 PL-45401 HCG55A 12.58 PL-45410 HC N57R 11.63 PL-45420 HC T104H 11.29 PL-45420 HCT104S 13.36 ¹Amino acid positions for the light chain (LC) are relativeto SEQ ID NO: 52 and amino acid positions for the heavy chain (HC) arerelative to SEQ ID NO: 191.

The mutations that provided increases in inhibitory potency against thehuman PAC1 receptor lie in three distinct regions of three dimensionalspace on the antibody surface. A second round of variant antibodies andFab-Fc fusion proteins were generated by combining mutations in thesethree regions to potentially provide additional increases in potency. Inaddition, some of the neutral mutations were incorporated as they werelikely to not have a significant effect on binding, but may providemechanisms to modify antibody biophysical characteristics. The variableregions containing the desired mutations were incorporated into abivalent monoclonal antibody having a human aglycosylated IgG1 Fc regionand/or a monovalent Fab-Fc fusion protein. The aglycosylated human IgG1antibody Fc region comprised the sequence of a human IgG1z Fc regionwith N297G, R292C, and V302C mutations according to EU numbering (SEQ IDNO: 325). The variant antibodies and Fab-Fc fusion proteins withcombinations of mutations were evaluated for functional activity in thecell-based cAMP assay. The results are shown in Table 12 below.

TABLE 12 In vitro inhibitory potency of variant antibodies and Fab-Fcfusion proteins Fab-Fc fusion protein functional activity mAb functionalactivity (monovalent (bivalent target binding) target binding)Substitutions with respect Substitutions with respect to Fold- Fold-Fold- Fold- to 29G4v10 VL sequence 29G4v10 VH sequence increase increaseincrease increase (SEQ ID NO: 52) (SEQ ID NO: 191) IC50 over over IC50over over Variant LC LC LC HC HC HC (SD) parental parental (SD) parentalparental Ab ID. CDR1 CDR2 CDR3 CDR1 CDR2 CDR3 in nM (on plate)¹ (avg)²in nM (on plate)¹ (avg)² iPS: 420649 Q27K — — — D54N — 0.18 6.4 4.3 0.7110.5 12.9 (0.04) (0.09) iPS: 420653 Q27K — — — D54I — 0.18 6.4 4.3 0.998.1 9.2 (0.06) (0.13) iPS: 420657 Q27K — — — D54Q — 0.29 2.5 2.7 0.879.2 10.4 (0.05) (0.23) iPS: 420661 Q27K — — — D54Y — 0.21 3.4 3.7 1.834.4 5.0 (0.05) (0.28) iPS: 420665 Q27K — — — G56R — 0.44 1.7 1.8 1.944.1 4.7 (0.19) (0.50) iPS: 420672 Q27K — — — G56N — 1.04 0.7 0.7 3.172.5 2.9 (0.50) (0.97) iPS: 420679 Q27K — — — E62R — 0.47 1.6 1.7 1.346.0 6.8 (0.22) (0.31) iPS: 420686 Q27K — — — — V102I 0.78 0.9 1.0 1.924.2 4.7 (0.39) (0.19) iPS: 420690 — — — — D54N; — 0.16 4.4 4.8 1.86 3.64.9 G56R (0.02) (0.17) iPS: 420697 — — — — D54I; — 0.20 3.4 4.0 1.48 4.56.1 G56R (0.06) (0.48) iPS: 420704 — — — — D54Q; — 0.18 3.7 4.4 2.00 3.44.5 G56R (0.05) (0.20) iPS: 420711 — — — — D54Y; — 0.45 1.5 1.7 3.45 1.92.6 G56R (0.29) (0.13) iPS: 420718 — — — — D54N; — 0.60 1.1 1.3 3.33 2.02.7 G56N (0.21) (0.63) iPS: 420725 — — — — D54I; — 0.56 1.2 1.4 4.06 1.72.2 G56N (0.04) (0.58) iPS: 420732 — — — — D54Q; — 0.74 0.9 1.1 1.82 3.75.0 G56N (0.18) (0.32) iPS: 420739 — — — — D54Y; — 0.63 1.1 1.2 2.76 2.93.3 G56N (0.13) (0.34) iPS: 420746 — — — — D54N; — 0.18 4.2 4.4 0.81 9.811.3 E62R (0.04) (0.13) iPS: 420753 — — — — D54I; — 0.16 4.8 5.0 1.555.1 5.9 E62R (0.05) (0.11) iPS: 420760 — — — — D54Q; — 0.32 2.4 2.5 2.702.9 3.4 E62R (0.06) (0.85) iPS: 420767 — — — — D54Y; — ND ND ND 1.49 5.36.1 E62R (0.54) iPS: 420774 — — — — D54N V102I 0.69 1.1 1.1 1.04 7.6 8.7(0.30) (0.20) iPS: 420781 — — — — D5RI V102I 0.40 1.9 1.9 1.81 4.4 5.0(0.05) (0.43) iPS: 420788 — — — — D54Q V102I 0.46 1.6 1.7 1.59 6.0 5.7(0.17) (0.83) iPS: 420795 — — — — D54Y V102I 0.50 1.5 1.5 4.25 2.3 2.1(0.09) (1.91) iPS: 420802 — — — — G56R; — 0.17 3.9 4.6 1.51 6.4 6.0 E62R(0.05) (0.01) iPS: 420809 — — — — G56N; — 0.77 0.9 1.0 2.51 3.8 3.6 E62R(0.20) (0.28) iPS: 420816 — — — — G56R V102I 0.50 1.3 1.6 2.44 3.9 3.7(0.07) (0.43) iPS: 420823 — — — — G56N V102I 1.41 0.5 0.6 2.30 4.2 3.9(0.42) (0.42) iPS: 420830 — — — — E62R V102I 0.91 0.7 0.9 1.73 5.5 5.3(0.64) (0.16) iPS: 420837 Q27K — — — D54N; — 0.21 3.2 3.7 0.67 12.4 13.5G56R (0.10) (0.18) iPS: 420841 Q27K — — — D54I; — 0.14 6.1 5.6 0.69 12.013.1 G56R (0.00) (0.10) iPS: 420845 Q27K — — — D54Q; — 0.12 7.5 6.8 0.8310.1 10.9 G56R (0.04) (0.14) iPS: 420849 Q27K — — — D54Y; — 0.22 4.0 3.61.73 4.8 5.2 G56R (0.04) (0.74) iPS: 420853 Q27K — — — D54N; — 0.39 2.22.0 1.93 4.3 4.7 G56N (0.06) (0.73) iPS: 420857 Q27K — — — D54I; — 0.471.8 1.7 1.94 4.3 4.7 G56N (0.13) (0.27) iPS: 420861 Q27K — — — D54Q; —0.43 2.0 1.8 1.13 7.4 8.1 G56N (0.01) (0.37) iPS: 420865 Q27K — — —D54Y; — 0.39 2.2 2.0 3.23 4.1 2.8 G56N (0.03) (1.03) iPS: 420869 Q27K —— — D54N; — ND ND ND 0.91 14.3 10.0 E62R (0.06) iPS: 420873 Q27K — — —D54I; — ND ND ND 1.34 9.8 6.8 E62R (0.40) iPS: 420877 Q27K — — — D54Q; —ND ND ND 1.64 8.0 5.5 E62R (0.51) iPS: 420881 Q27K — — — D54Y; — ND NDND 1.33 9.8 6.8 E62R (0.27) iPS: 420885 Q27K — — — D54N V102I 0.15 3.75.4 1.18 11.1 7.7 (0.01) (0.04) iPS: 420889 Q27K — — — D54I V102I 0.163.4 4.9 1.87 7.0 4.8 (0.01) (0.39) iPS: 420893 Q27K — — — D54Q V102I0.30 1.8 2.6 1.58 8.2 5.8 (0.08) (0.33) iPS: 420897 Q27K — — — D54YV102I 0.49 1.1 1.6 4.05 3.2 2.2 (0.18) (0.38) iPS: 420901 — — — — D54N;— ND ND ND 2.06 6.3 4.4 G56R; (0.61) E62R iPS: 420908 — — — — D54I; — NDND ND 1.46 8.9 6.2 G56R; (1.11) E62R iPS: 420915 — — — — D54Q; — ND NDND 0.81 15.9 11.2 G56R; (0.20) E62R iPS: 420922 — — — — D54Y; — ND ND ND1.01 12.9 9.0 G56R; (0.21) E62R iPS: 420929 — — — — D54N; — 0.12 4.5 6.50.84 13.9 10.8 G56N; (0.00) (0.27) E62R iPS: 420936 — — — — D54I; — 0.163.4 4.9 1.89 6.2 4.8 G56N; (0.01) (0.54) E62R iPS: 420943 — — — — D54Q;— 0.17 3.8 4.7 3.62 3.2 2.5 G56N; (0.01) (1.42) E62R iPS: 420950 — — — —D54Y; — 0.30 2.1 2.6 3.45 3.4 2.6 G56N; (0.06) (1.38) E62R iPS: 420957 —— — — D54N; V102I 0.27 2.3 2.9 2.83 4.1 3.2 G56R (0.01) (1.54) iPS:420964 — — — — D54I; V102I 0.37 1.7 2.1 2.86 4.1 3.2 G56R (0.09) (1.29)iPS: 420971 — — — — D54Q; V102I 0.22 2.8 3.5 3.52 3.3 2.6 G56R (0.00)(1.74) iPS: 420978 — — — — D54Y; V102I 0.28 2.3 2.8 5.24 2.7 1.7 G56R(0.01) (1.26) iPS: 420985 — — — — D54N; V102I ND ND ND 2.86 4.9 3.2 G56N(0.32) iPS: 420992 — — — — D54I; V102I 0.38 1.6 2.0 6.18 2.3 1.5 G56N(0.07) (0.84) iPS: 420999 — — — — D54Q; V102I 0.63 1.0 1.2 11.60  1.20.8 G56N (0.18) (1.89) iPS: 421006 — — — — D54Y; V102I 1.10 0.6 0.713.82  1.0 0.7 G56N (0.17) (1.13) iPS: 421013 — — — — G56R; V102I 0.322.0 2.4 2.07 6.8 4.4 E62R (0.03) (0.61) iPS: 421020 — — — — G56N; V102I0.54 1.2 1.5 2.65 5.3 3.4 E62R (0.01) (0.53) iPS: 421027 Q27K — — —D54N; — ND ND ND 0.91 12.5 10.0 G56R; (0.41) E62R iPS: 421031 Q27K — — —D54I; — ND ND ND 0.82 13.8 11.0 G56R; (0.31) E62R iPS: 421035 Q27K — — —D54Q; — ND ND ND 1.22 9.3 7.4 G56R; (0.29) E62R iPS: 421039 Q27K — — —D54Y; — ND ND ND 2.98 3.8 3.1 G56R; (2.17) E62R iPS: 421043 Q27K — — —D54N; — ND ND ND 1.44 7.9 6.3 G56N; (0.53) E62R iPS: 421047 Q27K — — —D54I; — 0.10 6.5 8.1 1.29 8.8 7.1 G56N; (0.00) (0.59) E62R iPS: 421051Q27K — — — D54Q; — 0.09 7.0 8.6 1.80 6.3 5.1 G56N; (0.01) (0.99) E62RiPS: 421055 Q27K — — — D54Y; — 0.43 1.6 1.8 1.06 7.7 8.6 G56N; (0.04)(0.18) E62R iPS: 421059 Q27K — — — D54N; V102I 0.10 6.8 7.8 1.01 8.1 9.0G56R (0.04) (0.07) iPS: 421063 Q27K — — — D54I; V102I 0.23 3.0 3.4 1.127.3 8.1 G56R (0.01) (0.12) iPS: 421067 Q27K — — — D54Q; V102I 0.30 2.32.6 1.49 5.5 6.1 G56R (0.04) (0.43) iPS: 421071 Q27K — — — D54Y; V102I0.30 2.3 2.6 1.18 6.9 7.7 G56R (0.14) (0.05) iPS: 421075 Q27K — — —D54N; V102I ND ND ND 1.02 8.0 8.9 G56N (0.21) iPS: 421079 Q27K — — —D54I; V102I 0.30 2.2 2.6 1.21 5.9 7.5 G56N (0.07) (0.04) iPS: 421083Q27K — — — D54Q; V102I 0.51 1.3 1.5 1.73 4.1 5.2 G56N (0.29) (0.03) iPS:421087 Q27K — — — D54Y; V102I 0.33 2.3 2.4 2.38 3.0 3.8 G56N (0.05)(0.63) iPS: 421091 — — — — D54N; V102I 0.07 11.4 11.7 1.41 5.1 6.5 G56R;(0.00) (0.26) E62R iPS: 421098 — — — — D54I; V102I 0.17 4.6 4.7 1.26 5.77.2 G56R; (0.01) (0.14) E62R iPS: 421105 — — — — D54Q; V102I 0.19 4.04.1 1.12 6.4 8.1 G56R; (0.04) (0.17) E62R iPS: 421112 — — — — D54Y;V102I 0.21 3.6 3.7 1.38 5.2 6.6 G56R; (0.01) (0.33) E62R iPS: 421119 — —— — D54N; V102I 0.21 3.6 3.7 1.20 9.6 7.6 G56N; (0.00) (0.17) E62R iPS:421126 — — — — D54I; V102I 0.19 4.0 4.1 1.95 5.9 4.7 G56N; (0.01) (0.14)E62R iPS: 421133 — — — — D54Q; V102I 0.29 3.1 2.7 4.46 2.6 2.0 G56N;(0.05) (1.18) E62R iPS: 421140 — — — — D54Y; V102I 0.37 2.4 2.1 5.48 2.11.7 G56N; (0.04) (1.06) E62R iPS: 421147 Q27K — — — D54Y; V102I 1.15 0.80.7 1.81 6.4 5.0 G56N; (0.80) (0.47) E62R iPS: 421151 G30W — — — — —6.66 0.1 0.1 12.50  0.9 0.7 (2.26) (3.25) iPS: 391478 S32N — — — — —6.16 0.1 0.1 36.74  0.3 0.2 (3.39) (9.14) iPS: 421157 — — R93M — — —8.04 0.1 0.1 6.60 2.0 1.4 (3.91) (1.31) iPS: 421163 — — — R31H — —14.01  0.1 0.1 4.99 2.6 1.8 (8.21) (0.69) iPS: 391578 — — — F32Y — —2.68 0.3 0.3 4.91 2.7 1.9 (1.22) (0.37) iPS: 421170 — — — — Y53F — 3.180.2 0.2 4.56 2.9 2.0 (0.65) (0.87) iPS: 421176 — — — — G56A — 3.03 0.20.3 ND ND ND (0.57) iPS: 421182 — — — — — V102F 1.50 0.5 0.5 5.47 2.41.7 (0.72) (0.37) iPS: 421189 Q27K; — — — — — 0.65 1.1 1.2 7.48 1.7 1.2G30W (0.31) (0.45) iPS: 421195 Q27K; — — — — — 0.65 1.1 1.2 5.28 1.3 1.7S32N (0.24) (0.46) iPS: 421201 Q27K — R93N — — — 1.70 0.4 0.5 4.63 1.42.0 (0.37) (0.88) iPS: 421207 Q27K — — R31H — — 3.68 0.2 0.2 8.27 0.81.1 (0.64) (1.17) iPS: 421211 Q27K — — F32Y — — 1.67 0.4 0.5 4.25 1.62.1 (0.32) (0.21) iPS: 421215 Q27K — — — Y53F — 1.39 0.5 0.6 3.24 2.02.8 (0.21) (0.20) iPS: 421219 Q27K — — — G56A — 1.19 0.6 0.7 ND ND ND(0.51) iPS: 421223 Q27K — — — — V102F 0.60 1.2 1.3 6.30 1.1 1.4 (0.09)(0.04) iPS: 421227 G30W — — — D54N — 0.39 1.9 2.0 5.02 1.3 1.8 (0.06)(1.29) iPS: 421231 S32N — — — D54N — 0.51 1.7 1.5 6.39 1.1 1.4 (0.11)(1.58) iPS: 421235 — — R93M — D54N — 1.45 0.6 0.5 0.00 — — (0.18) (0.00)iPS: 421239 — — — R31H D54N — 3.87 0.2 0.2 4.28 1.6 2.1 (0.10) (0.56)iPS: 421246 — — — F32Y D54N — 0.64 1.3 1.2 3.36 2.1 2.7 (0.17) (0.50)iPS: 421253 — — — — Y53F; — 0.38 2.3 2.0 2.88 2.4 3.2 D54N (0.10) (0.17)iPS: 421260 — — — — D54N; — 0.43 2.0 1.8 2.85 2.4 3.2 G56A (0.16) (0.12)iPS: 421267 — — — — D54N V102F 0.23 4.0 3.5 3.51 2.0 2.6 (0.01) (0.16)iPS: 421274 G30W — — — G56R — 0.61 1.5 1.3 5.12 1.4 1.8 (0.04) (0.45)iPS: 421278 S32N — — — G56R — 0.90 1.0 0.9 11.96  1.1 0.8 (0.14) (6.93)iPS: 421282 — — R93M — G56R — 1.12 0.8 0.7 6.99 1.9 1.3 (0.25) (0.40)iPS: 421286 — — — R31H G56R — 2.92 0.3 0.3 4.11 3.2 2.2 (0.50) (0.38)iPS: 421293 — — — F32Y G56R — 0.91 1.0 0.9 4.30 3.1 2.1 (0.08) (0.42)iPS: 421300 — — — — Y53F; — 1.10 0.8 0.7 4.05 3.3 2.2 G56R (0.15) (0.88)iPS: 421307 — — — — G56R V102F 0.28 2.3 2.8 4.35 3.0 2.1 (0.02) (0.04)iPS: 421314 G30W — — — E62R — 0.52 1.2 1.5 5.09 2.6 1.8 (0.02) (0.49)iPS: 421318 S32N — — — E62R — 0.73 0.9 1.1 4.48 1.7 2.0 (0.16) (0.28)iPS: 421322 — — R93M — E62R — 1.23 0.5 0.6 3.49 2.2 2.6 (0.47) (0.28)iPS: 421326 — — — R31H E62R — 3.70 0.2 0.2 4.29 1.8 2.1 (0.28) (0.81)iPS: 421333 — — — F32Y E62R — 1.05 0.6 0.7 1.23 6.3 7.4 (0.08) (0.10)iPS: 421340 — — — — Y53F; — 0.71 0.9 1.1 1.44 5.4 6.3 E62R (0.21) (0.01)iPS: 421347 — — — — G56A; — 0.71 1.1 1.1 1.32 5.9 6.9 E62R (0.13) (0.45)iPS: 421354 — — — — E62R V102F 0.53 1.5 1.5 2.33 2.8 3.9 (0.01) (0.67)iPS: 421361 G30W — — — — V102I 1.29 0.6 0.6 2.11 3.1 4.3 (0.72) (0.11)iPS: 421365 S32N — — — — V102I 4.46 0.2 0.2 8.87 0.7 1.0 (0.43) (0.57)iPS: 421369 — — R93M — — V102I 6.43 0.1 0.1 4.58 1.4 2.0 (3.20) (0.38)iPS: 421373 — — — R31H — V102I 9.82 0.1 0.1 3.19 2.0 2.8 (0.36) (0.13)iPS: 421380 — — — F32Y — V102I 3.28 0.2 0.2 3.09 2.1 2.9 (0.59) (0.40)iPS: 421387 — — — — Y53F V102I 1.78 0.6 0.4 2.45 2.7 3.7 (0.32) (0.21)iPS: 421394 — — — — G56A V102I 2.36 0.4 0.3 1.65 4.0 5.5 (0.20) (0.64)¹This value represents the fold-increase in IC50 as compared to the IC50value for the 29G4v10 parental molecule formatted as either a mAb orFab-Fc fusion protein that was run in parallel with each variantmolecule. ²This value represents the fold-increase in IC50 as comparedto the average IC50 value for the 29G4v10 parental molecule formatted aseither a mAb or Fab-Fc fusion protein ND = not determined

The greatest improvements in potency were observed when the antibodieshad a mutation at position Q27 (Q27K) in the light chain variable regionand a mutation at position D54 (D54I, D54Q, or D54N) and/or position G56(G56R or G56N) in the heavy chain variable region. Q27 in the lightchain variable region of SEQ ID NO: 52 corresponds to amino acidposition 29 in AHo numbering. D54 and G56 in the heavy chain variableregion of SEQ ID NO: 191 correspond to amino acid positions 61 and 66 inAHo numbering, respectively. A basic amino acid, such as lysine orarginine, at position Q27 in the light chain variable region presumablyprovides improved charge complementarity with acidic amino acids Glu120and Asp121 in the PAC1 ECD (see Zone 1 in FIG. 2A). Hydrophobic residues(e.g. isoleucine) or neutral hydrophilic residues (e.g. glutamine orasparagine) at position D54 in the heavy chain variable region and basicresidues (e.g. arginine) or neutral hydrophilic residues (e.g.asparagine) at position G56 in the heavy chain variable region appear toimprove the hydrophobic interaction or hydrogen bonding with amino acidresidues Asn60 and Ile61 in the PAC1 ECD (see Zone 6 in FIG. 3B).

The top eleven mutants from the MutHC library screen (Table 8) wereformatted as aglycosylated IgG1 monoclonal antibodies and monovalentFab-Fc molecules as described above for production and functionaltesting in the cAMP assay (Table 13). The modestly improved binding onyeast for this set of variants translated to improved PAC1 receptorblocking function for four out of 11 mAbs and seven out of 11 Fab-Fcs.Nevertheless, as an antibody, the iPS:421873 mutant showed about a4-fold improvement in PAC1 blocking function compared to parental29G4v10 antibody. Activity rankings of the mutants were largelyconsistent across the two formats, with the Fab-Fcs consistently showingweaker function (higher IC50 values) than the mAbs, presumably due toloss of avidity.

TABLE 13 In vitro inhibitory potency of variants from the MutHC libraryscreen Fab-Fc fusion protein functional activity mAb functional activity(monovalent (bivalent target binding) target binding) Substitutions withrespect Substitutions with respect to Fold- Fold- Fold- Fold- to 29G4v10VL sequence 29G4v10 VH sequence increase increase increase increase (SEQID NO: 52) (SEQ ID NO: 191) IC50 over over IC50 over over Variant LC LCLC HC HC HC (SD) parental parental (SD) parental parental Ab ID. CDR1CDR2 CDR3 CDR1 CDR2 CDR3 in nM (on plate)¹ (avg)² in nM (on plate)¹(avg)² iPS: 421855 — — — R31K; Y53F; V102L 0.55 1.8 1.4 1.30 5.1 7.0F32Y D54K (0.11) (0.02) G56S iPS: 421861 — — — F32Y D54Q V102L 1.29 0.80.6 3.31 2.0 2.7 (0.22) (0.66) iPS: 421867 — — — R31H Y53F; V102M 5.550.2 0.1 5.41 1.2 1.7 D54S; (0.49) (0.25) G56S iPS: 421873 — — — R31KD54R V102L 0.25 3.9 3.1 1.27 5.2 7.1 (0.04) (0.03) iPS: 421879 — — —F32Y D54S; V102L; 1.60 0.6 0.5 2.06 3.2 4.4 G56A T104S (0.01) (0.75)iPS: 421885 — — — R31H; Y53F; V102L 0.72 1.3 1.1 2.51 2.6 2.6 F32Y D54K;(0.14) (0.58) G56A iPS: 421891 — — — R31H; D54R; V102L 1.04 0.9 0.8 2.592.9 3.5 F32Y G56A (0.09) (0.24) iPS: 421897 — — — R31H; Y53F; V102F 3.420.3 0.2 5.85 1.3 1.6 F32Y D54Y; (0.41) (0.71) G56S iPS: 421903 — — —R31H Y53F; V102F 2.34 0.4 0.3 4.95 1.5 1.8 D54F (0.98) (0.23) iPS:421909 — — — R31H; Y53F; V102F 4.10 0.2 0.2 5.01 1.5 1.8 F32Y D54M;(0.36) (2.10) G56T iPS: 421915 — — — R31Y Y53H; V102L; 0.80 1.2 1.0 2.383.1 3.8 D54R; T104S (0.00) (0.69) G56T ¹This value represents thefold-increase in IC50 as compared to the IC50 value for the 29G4v10parental molecule formatted as either a mAb or Fab-Fc fusion proteinthat was run in parallel with each variant molecule. ²This valuerepresents the fold-increase in IC50 as compared to the average IC50value for the 29G4v10 parental molecule formatted as either a mAb orFab-Fc fusion protein

A subset of the 29G4v10 mutants from the chain-shuffled libraries(Tables 9 and 10) were converted to aglycosylated IgG1 monoclonalantibodies and tested for functional activity in the cell-based cAMPassay. The results are shown in Table 14 below.

TABLE 14 In vitro inhibitory potency of variants from chain-shuffledyeast display libraries Variant Ab Human PAC1 Rat PAC1 Clone ID ID. IC50(nM) SD IC(nM) SD 30_D05 iPS:480711 0.07 0.00 0.17 0.02 37_F04iPS:480706 0.42 0.01 0.66 0.08 37_A11 iPS:480713 0.50 0.05 1.22 0.4037_H05 iPS:480705 0.53 0.25 1.16 0.34 37_B06 iPS:480707 0.59 0.01 1.170.26 30_H10 iPS:480708 0.62 0.02 1.06 0.13 30_F08 iPS:480709 0.77 0.171.82 0.97 30_E08 iPS:480712 0.83 0.33 1.68 0.92 37_E09 iPS:480704 1.360.05 2.74 1.05 30_A05 iPS:480710 1.61 0.20 3.53 1.00 1_D07 iPS:4807162.51 0.43 5.22 2.08 2_C11 iPS:480715 3.63 1.04 7.37 2.73 2_G07iPS:480717 3.92 0.86 10.77 0.73 2_B10 iPS:480714 10.15 2.12 41.05 23.7729G4v10 0.75 84.50² parental antibody 29G4v22 4.70 >1000 control¹¹29G4v22 is another anti-PAC1 neutraizing antibody that sharessignificant structural similarity with 29G4v10. The VL and VH sequencesfor 29G4v22 are provided in SEQ ID NOs: 53 and 192 respectively.²Historical value obtained from a previous assay and included forcomparative purposes.

When formatted as monoclonal antibodies (mAbs), 29G4v10 mutants from thesecond generation chain-shuffled library (Table 10) were more potentantagonists of PAC1 than mutants from the first generationchain-shuffled library (Table 9), suggesting that enhanced PAC1 blockingfunction is correlated with improved binding and slower bindingoff-rates, in particular. However, surprisingly, most of the mutants asmAbs were less active than antibody iPS:421873, the most potent mutantfrom the mutHC library screen (Table 13), despite their presumablyenhanced binding to the human PAC1 ECD. Nevertheless, the 30_D05 mutantexhibited about a 10-fold and 67-fold improvement in function ascompared to the 29G4v10 parental antibody and 29G4v22 control antibody,respectively. One common feature shared by the highly potent S8_30_D05and iPS:421873 mAbs is the D54R mutation within HCDR2, which is absentin all of the other less potent mAb mutants. Interestingly, all of theaffinity-matured variants exhibit cross-reactivity with the rat PAC1receptor, in contrast to the 29G4v10 parental antibody and 29G4v22control antibody (Table 14).

Example 4. In Vivo Functional Activity of Human PAC1 Antibody Variants

Maxadilan is a vasodilatory peptide and an agonist of the PAC1 receptor.When administered intradermally, maxadilan causes an increase in localdermal blood flow that can be measured by laser Doppler imaging.Inhibition of this effect by PAC1 antagonists (e.g. anti-PAC1antibodies) can serve as a translational pharmacodynamic model ofantagonism of PAC1 biological activity. A subset of the PAC1 variantsthat exhibited improved in vitro inhibitory potency when formatted asmonoclonal antibodies from Example 3 were tested for efficacy ininhibiting PAC1 receptor activation in vivo by using a rat dermal bloodflow model.

In Vivo Pharmacodynamic Model

Naive male Sprague Dawley rats aged at 8-12 weeks at the time of thestudy were purchased from Charles River Laboratories. All procedures inthis example were conducted in compliance with the Animal Welfare Act,the Guide for the Care and Use of Laboratory Animals, and the Office ofLaboratory Animal Welfare. Animals were group-housed in non-sterile,ventilated micro-isolator housing in Amgen's Assessment andAccreditation of Laboratory Animal Committee (AAALAC)-accreditedfacility. Animals had ad libitum access to pelleted feed (Harlan Teklad2020X, Indianapolis, Ind.) and water (on-site generated reverse osmosis)via automatic watering system.

The subset of anti-PAC1 antibodies were tested in a ratmaxadilan-induced increase in dermal blood flow (MIIBF) pharmacodynamic(PD) model with a laser Doppler imaging. A dosing solution of maxadilan(Bachem, H6734.0500) was prepared fresh daily by diluting maxadilanstock solution (0.5 mg/mL) in 1× phosphate-buffered saline (PBS) to afinal concentration of 0.5 μg/mL. All anti-PAC1 antibodies (Abs) wereprepared in 10 mM sodium-acetate, 9% sucrose, pH 5.2 (A52Su) atdifferent concentrations, depending on the dose required for theexperiment, and administered via a single bolus i.v. injection one dayprior to the dermal blood flow (DBF) measurement by the laser Dopplerimaging.

A laser Doppler imager (LDI-2, Moor Instruments, Ltd, Wilmington, Del.)was used to measure DBF on a shaved patch of skin of the rat abdomenusing a low-power laser beam generated by a 633 nm helium-neon bulb. Themeasurement resolution was 0.2 to 2 mm, with a scanning distance betweenthe instrument aperture and the tissue surface of 30 cm. DBF wasmeasured and expressed as either % change from baseline [100×(individual post-maxadilan flux-individual baseline flux)/individualbaseline flux] or % DBF inhibition [Mean of vehicle % change fromBL−individual antibody treated rat % change from BL)/Mean of vehicle %change from BL] to quantify the magnitude of the antibody effect.

On the test day, following anesthetization with propofol, the rat'sabdominal area was shaved and each animal was placed in a supineposition on a temperature-controlled circulating warm-water pad tomaintain a stable body temperature during the study. After a 10 to 15minute stabilization period, a rubber O-ring (0.925 cm inner diameter,O-Rings West, Seattle, Wash.) was placed on the rat abdomen (withoutdirectly positioning it over a visible blood vessel). After placement ofthe O-ring on the selected area, a baseline (BL) DBF measurement wastaken. After the BL scan, the PAC1 agonist maxadilan was administered byintradermal injection (20 μL of 0.5 μg/mL) at the center of the O-ring.DBF was measured 30 min following maxadilan injection, or 24±1.5 hoursfollowing antibody treatment. The O-ring defines the area of interest inwhich the DBF was analyzed.

All DBF results were expressed as the mean±SEM. A one-way ANOVA followedby Dunnett's Multiple Comparison Test (MCT) was used to assess thestatistical significance of PAC1 Ab effects relative to vehicletreatment. A p value of <0.05 was used to determine significance betweentwo groups.

Single Intravenous (i.v.) Dose Screening Evaluation

Rats were pretreated with one of 7 different anti-PAC1 antibodies(420653, 420845, 420943, 421873, 420889 (PL-50347), 421091 (PL-50350),and 421051 (PL-50351)) 24 hours prior to maxadilan challenge (20 μl of0.5 μg/mL) at a dose of 0.1 mg/kg or 0.3 mg/kg, which resulted in areduction in MIIBF compared to vehicle (A52Su) treated group. At 30 minpost-maxadilan treatment, there was a statistically significantinhibition in MIIBF at 0.3 mg/kg compared to the vehicle group for fiveof the seven antibodies tested (FIG. 6). Terminal serum concentration at24±1.5 hours for six of the seven antibodies is listed in Table 15below.

TABLE 15 Terminal serum concentrations for single-injection (screening)study Dose (mg/kg) Antibody ID. 0.1 0.3 420653 (PL-50345) 2.0 ± 0.8  8.9± 2.5 420845 (PL-50346) 1.2 ± 0.3  6.4 ± 0.8 420889 (PL-50347) 5.5 ± 3.110.7 ± 1.7 420943 (PL-50348) 1.6 ± 0.4  8.9 ± 1.8 421873 (PL-50349) 1.1± 0.3  4.4 ± 0.4 421091 (PL-50350) 1.0 ± 0.1  3.0 ± 0.1Dose-Response Evaluation

Rats were pretreated with 4 different anti-PAC1 antibodies (420653,420845, 420943, and 421873) 24 hours prior to maxadilan challenge (20 μlof 0.5 pg/mL) at a dose ranging from 0.01 mg/kg to 30 mg/kg. Adose-dependent reduction of MIIBF compared to vehicle-treated group wasobserved for each of the four antibodies (FIGS. 7A-7D). Ab 420653produced a significant effect at a dose as low as 0.06 mg/kg withinhibitory effects of 44%, 68%, 86%, 95%, and 101% at 0.06, 0.1, 0.3, 1and 3 mg/kg, respectively (FIG. 7A). Ab 420845 produced a significanteffect at 0.3, 1 and 3 mg/kg with inhibition of 79% 102% and 107%,respectively (FIG. 7B). Ab 420943 and 421873 were slightly less potentthan Ab 420845 and Ab 420653, but still produced a significantinhibitory effect at 1 mg/kg. The % inhibition in DBF for Ab 420943 was56%, 46%, 52% and 81% at 1, 3, 10, 30 mg/kg, respectively (FIG. 7C). The% inhibition in DBF for Ab 421873 was 34%, 55%, 72% and 100% at 1, 3,10, and 30 mg/kg, respectively (FIG. 7D).

The results of the experiments described in this example show thatantibodies that potently inhibit ligand-induced PAC1 receptor activationin vitro also inhibit PAC1 receptor activation in vivo as assessed bythe dermal blood flow assay, a model of PAC1-mediated vasodilation.

Example 5. Pharmacokinetic Characteristics of Human PAC1 AntibodyVariants

Preliminary pharmacokinetic (PK) studies of four anti-PAC1 antibodies(420653, 420845, 420943, and 421873) were conducted with naïve maleSprague-Dawley rats and naïve male cynomolgus monkeys. The 29G4v10parental antibody or the structurally related 29G4v22 antibody (VLcomprising SEQ ID NO: 53 and VH comprising SEQ ID NO: 192) was evaluatedas a control. The test antibodies were dosed to study animals byintravenous bolus administration. Blood samples were collected atspecified time points post-dose and processed to serum. All serumspecimens were stored at approximately −70° C. (±10° C.) untiltransferred for subsequent analysis.

To measure the amount of test antibody in serum samples from rats andcynomolgus monkeys following dosing, a colorimetric enzyme-linkedimmunosorbent assay (ELISA) was developed using murine monoclonalantibodies (mAb) directed against human IgG Fc (Amgen, Inc., CA, USA).Microtiter plates were coated with a murine anti-human Fc mAb at 2μg/mL. The coated microtiter plates were blocked with I-block (AppliedBiosystems, CA, USA). Assay standards (STDs) and quality controls (QCs)were prepared by spiking the test antibody into 100% serum from thestudied species. STDs, QCs, blank and study samples were diluted 1:30 inassay buffer (1×PBS with 1 M NaCl, 1% BSA and 0.5% Tween 20). DilutedSTDs, QCs, blank and study samples were incubated on the coatedmicrotiter plates for 1 h at 25° C. without agitation. After a washstep, a horseradish peroxidase (HRP)-conjugated murine anti-human Fc mAbat 30 ng/mL in assay buffer was added to the microtiter plates andincubated for 1 h at 25° C. without agitation. After a final wash step,a tetramethylbenzidine (TMB) peroxide substrate solution (KPL Inc., MD,USA) was added to the microtiter plates. In the presence of HRP, TMBproduced a colorimetric signal that was proportional to the quantity ofbound human Fc present in the STDs, QCs and study samples. The colordevelopment duration was analyte-dependent and was stopped by additionof 2N sulfuric acid. The optical density (OD) was measured at 450 nmwith reference to 650 nm using a SpectraMax 340PC microtiter platereader (Molecular Devices, CA, USA) and SoftMax Pro software. Assay datawere regressed using a logistic (auto-estimate) regression model with aweighting factor of 1/y. The assay dynamic range was from 20 ng/mL to2000 ng/mL.

For both the rat and cynomolgus monkey PK studies, noncompartmentalanalysis was performed on individual serum concentration-nominal timedata using Phoenix® WinNonlin® (version 6.4; Certara, N.J., USA).Individual concentration values less than the lower limit ofquantification (LLOQ, 20 ng/mL) were reported as below the quantitationlimit (BQL) and set to zero for the calculation of summary statistics.Mean concentration values less than the LLOQ were not reported orplotted. All concentrations values less than the LLOQ were excluded fromthe noncompartmental analysis. Nominal doses and nominal sampling timeswere used for PK analysis. The following PK parameters were estimated:

-   -   The initial concentration (C₀) value after intravenous        administration was estimated by back extrapolation to time zero        using the first 2 observed declining concentration values.    -   The area under the concentration-time curve from time zero to        infinity (AUCinf) was calculated by the linear trapezoidal        method.    -   The terminal-phase half-life (t_(1/2,z)) was calculated as ln        2/λ_(z). λ_(z) is the first-order rate constant of drug        associated with the terminal portion of the curve.    -   Systemic clearance (CL) was calculated as: CL=Dose/AUCinf after        intravenous administration    -   Volume of distribution at steady state (Vss) was estimated as:        Vss=CL×MRTinf (mean residence time from time zero to infinity)

A summary of the in vitro inhibitory potency of the four antibodies aswell as for the 29G4v10 parental antibody and the 29G4v22 controlantibody against the human PAC1, rat PAC1, and cyno PAC1 is provided inTable 16 below. The antibodies were evaluated for the ability to inhibitligand-induced (PACAP38 or maxadilan) activation of the PAC1 receptorfrom different species using the cAMP assay described in Example 3.

TABLE 16 Summary of In Vitro Inhibitory Potency for PAC1 VariantAntibodies Human PAC1 (nM) Cyno PAC1 (nM) Rat PAC1 (nM) PACAP38Maxadilan PACAP38 Maxadilan PACAP38 Maxadilan Antibody ID (n = 3) (n =3) (n = 3) (n = 3) (n = 3) (n = 2) 420653 0.24 0.13 0.13 0.10 0.21 0.19420845 0.09 0.09 0.08 0.09 0.11 0.07 420943 0.37 0.20 0.21 0.17 5.660.69 421873 0.24 0.10 0.12 0.10 0.23 0.06 29G4v22 4.70 1.60 1.111.00 >1000 580 29G4v10 0.75 — 0.33 — 84.5 8.75

Rats were administered intravenously one of the four antibodies at adose of 1 mg/kg, 5 mg/kg, and 25 mg/kg. Blood samples were collected atvarious time points after dosing and antibody concentration was measuredin serum samples at each of the time points using the ELISA assaydescribed above. PK parameters for the rat study are summarized in Table17 below and serum concentration-time profiles for each of the doses areshown in FIGS. 8A-8C.

TABLE 17 Summary of PK Parameters for PAC1 Variant Antibodies in RatsAnti- IV body Dose C₀ AUC_(0-inf) V_(ss) CL t_(1/2,z) ID (mg/kg) n(μg/mL) (μg*hr/mL) (mL/kg) (mL/hr/kg) (hr) 420653 1 3 19.6 467 100 2.1635.3 5 3 87.1 2600 218 2.05 70.5 25 2 462 16900 236 1.48 130 420845 1 315.7 305 141 3.28 42.2 5 3 104 2420 171 2.08 73.2 25 2 525 14800 1791.69 100 420943 1 3 17.4 441 129 2.28 51.3 5 3 101 2900 184 1.75 79.3 252 490 13600 191 1.83 67.9 421873 1 3 11.2 179 156 5.88 27.9 5 3 64.21100 424 4.73 110 25 2 341 5300 383 4.73 96.8

Cynomolgus monkeys were administered intravenously one of the fourantibodies at a dose of 10 mg/kg. Blood samples were collected atvarious time points after dosing and antibody concentration was measuredin serum samples at each of the time points using the ELISA assaydescribed above. PK parameters for the cynomolgus monkey study aresummarized in Table 18 below and the serum concentration-time profilesare shown in FIG. 9. The PK profile of the 29G4v22 antibody is show forcomparison.

TABLE 18 Summary of PK Parameters for PAC1 Variant Antibodies inCynomolgus Monkeys Antibody C₀ AUC_(0-inf) V_(ss) CL t_(1/2,z) ID n(μg/mL) (μg*hr/mL) (mL/kg) (mL/hr/kg) (hr) 420653 3 274 14800 110 0.692134 420845 3 314 4870 126 2.09 85.3 420943 3 240 10000 126 1.00 107421873 3 245 11800 96.7 0.849 92.6 29G4v22 6 312 24000 43.3 0.443 70.3

At this dose, all four of the PAC1 variant antibodies had a longer serumhalf-life than the 29G4v22 control antibody. Interestingly, although allfour PAC1 variant antibodies exhibited greater in vitro inhibitorypotency against the PAC1 receptor as compared with the 29G4v22 controlantibody (Table 16), the PK profile for some of the variants was lessfavorable in cynomolgus monkeys. For example, Ab 420845 had a fasterclearance rate and lower overall exposure as compared to the 29G4v22control antibody. However, Ab 420653 had a comparable PK profile to thatfor the 29G4v22 control antibody (FIG. 9), suggesting that Ab 420653could be administered at a lower dose at the same dosing frequency toachieve a similar pharmacological effect.

Example 6. Yeast Display Affinity Maturation of 19118 Human PAC1Antibody

To generate additional anti-PAC1 antibodies with improved inhibitorypotency, the 19H8 antibody (VH region of SEQ ID NO: 296; VL region ofSEQ ID NO: 67) was affinity matured by FACS of yeast-displayed Fablibraries using the methods described in Example 2. The 19H8 antibody isstructurally diverse from the 29G4v9, 29G4v10, and 29G4v22 antibodies,but also exhibits very potent neutralizing activity against the humanPAC1 receptor.

Because no crystal structural information was available for the PAC1ECD-19H8 Fab complex initially, a homology model was generated toidentify the surface-exposed residues within each CDR loop. Because itis expected that the PAC1 ECD would make direct contacts withsurface-exposed CDR residues, it was hypothesized that changing thenature of these contacts or creating new contacts through comprehensivemutagenesis could lead to improved binding of the antibody to the PAC1ECD. To restrict theoretical diversities of each library to a manageable10⁶-10⁷, up to five positions per CDR were identified for MIX19saturation mutagenesis and one separate library per CDR was constructed.Due to concerns regarding the accuracy of modeled CDRH3 loopconformations, the most solvent-exposed residues within this loop couldnot be reliably identified. Therefore, diversification at eight of the11 CDR residues within CDRH3 were considered, excluding residues at thebeginning and end of the loop. To narrow down the number of positionsfor saturation mutagenesis to five, the two tryptophans and onephenylalanine within CDRH3 was avoided, as aromatic residues are oftencritical mediators of protein-protein interactions. In total, sixindividual-CDR Fab libraries were designed to target 16 heavy chain and15 light chain CDR residues for diversification, and the constructedlibraries oversampled the theoretical diversities by 4.5 to 46-fold. Asummary of the targeted positions for each CDR library is providedbelow:

Heavy chain CDR libraries (amino acid positions relative to SEQ ID NO:296):

-   -   CDRH1 library: Asp27 (located adjacent to CDRH1 in FR1), Ser31,        Asn32, Ser33, and Thr35    -   CDRH2 library: Tyr54, Tyr55, Ser57, Lys58, Ser60, and His62    -   CDRH3 library: Thr103, Lys105, Gln106, Leu107, and Leu110

Light chain CDR libraries (amino acid positions relative to SEQ ID NO:67):

-   -   CDRL1 library: Ser28, Ser30, Arg31, Tyr32, and Asn34    -   CDRL2 library: Tyr49 (located adjacent to CDRL2 in FR2), Ala50,        Ala51, Ser52, and Ser53    -   CDRL3 library: Ser91, Tyr92, Ser93, Pro94, and Phe96

The six individual-CDR Fab libraries were enriched for binding to humanPAC1 ECD using FACS, increasing the stringency with each successiveround by lowering the concentration of the PAC1 ECD used for binding(Round 1: 30 nM PAC1 ECD; Round 2: 0.67 nM PAC1 ECD; and Round 3: 0.2 nMPAC1 ECD). For further affinity improvements, two CDR-shuffled Fablibraries that combined enriched mutations from the individual CDRlibraries (one for the heavy chain and one for the light chain) and afinal chain-shuffled library that combined enriched mutations from eachCDR-shuffled library were also constructed. The CDR-shuffled andchain-shuffled libraries were subjected to selections for PAC1 ECDbinding under more stringent conditions using the off-rate bindingselection process described in Example 2 and depicted in FIG. 5. Thefinal off-rate sort of the chain-shuffled library suggested that most ofthe yeast clones within this pool were significantly improved in PAC1ECD binding compared to parental 19H8 antibody.

Approximately 800 individual yeast clones were screened for improvedbinding to human PAC1 ECD. Mutant sequences with sequence liabilities(e.g. cysteine anomalies, N-linked glycosylation sites, aspartateisomerization, asparagine deamidation, and tryptophan oxidation sites)were removed. The top ˜200 unique binders were advanced to a secondaryscreen where they were ranked by binding off-rate and evaluated fornon-specific binding. In the secondary screen, >80% of the clones hadslower binding off-rates than the parental 19H8 antibody, as measured bya higher association percentage of biotinylated human PAC1 ECD followingan overnight competition with unlabeled PAC1 ECD at 30° C. Themeasurements represent lower limits on the improvement in off-rate, asbiotinylated PAC1 ECD fully dissociated from parental 19H8 after onlyone hour of competition at 30° C. Because none of the screened clonesexhibited binding to the ECDs of unrelated PD1 and GIPR receptors, tofurther narrow down the pool of clones, additional sequence filters wereapplied to remove mutants whose CDRs contained furin cleavage sites,additional tryptophan residues, and more covariance violations than theparental 19H8 antibody. An additional binding assay using a biotinylatedhuman VPAC2 ECD to determine the degree of non-specific binding to humanVPAC2, a structurally related receptor to human PAC1 receptor, was usedto rank clones. The top 20 mutants exhibiting the slowest bindingoff-rates to human PAC1 ECD and the least amount of human VPAC2 bindingamong the yeast clones that entered the secondary screen are listed inTable 19 below. Higher percentage association of PAC1 ECD bindingindicates that the mutant Fabs have a slower off-rate.

TABLE 19 Top Improved Binders from Yeast Display Libraries for 19H8Parental Antibody Substitutions with respect Substitutions with respect% human to 19H8 VH sequence to 19H8 VL sequence PAC1 ECD Biotinylated(SEQ ID NO: 296) (SEQ ID NO: 67) association VPAC2 ECD HC LC afteroff-rate Binding Variant FR1 - HC HC LC FR2 - LC competition(fluorescence Ab ID. CDR1 CDR2 CDR3 CDR1 CDR2 CDR3 at 30° C. units) iPS:448202 S31N; S57G; K105N; — Y49F; S91A; 86% 562 N32R; S60K L107D A51G;Y92I; S33L S52Q; S93G; S53R P94M; F96Y iPS: 449375 S31N; S57G; K105D;S28Y; S52H; S91A; 80% 506 N32R; S60K L107D S30V S53H Y92I; S33L S93Q;P94E; F96Y iPS: 448083 N32R; S57G; K105E; S28T; Y49F; S91A; 75% 573 S33QS60K L107D S30V A51G; Y92I; S52Q; S93I; S53R P94N; F96Y iPS: 452128S31N; S57G; T103M; S28Y; S52N; S91A; 74% 535 N32K; S60K K105N; S30V S53MY92I; S33Q L107N S93N; P94Q; F96Y iPS: 448195 S31N; S57G; T103M; S28K;S52N; Y92I; 70% 577 N32K; S60K K105N; S30A; S53M S93Q; S33Q L107N N34VP94Q; F96Y iPS: 448466 S31N; S57G; K105I; — Y49F; S91A; 66% 510 N32K;K58Q; Q106G; A51G; Y92I; S33Q S60K L107D; S52Q; S93Q; L110M S53R P94Q;F96Y iPS: 448689 S31N; S57G; K105N; S28Y; A51S; S91A; 66% 596 N32R; S60KL107D S30V S52Y; Y92I; S33L S53N S93M; P94A; F96Y iPS: 449034 S31N;S57G; K105I; S28P; A51G; S91A; 65% 519 N32K; S60K L107D S30A; S52R;Y92I; S33Q R31Q S53Y S93Q; P94N; F96Y iPS: 448568 N32R; S57G; T103M; —A51G; S91A; 63% 620 S33Y S60K K105A; S52L; Y92I; Q106G; S53Y S93Q;L107D; P94T; L110M F96Y iPS: 448924 N32R; S57G; T103M; S28P; Y49F; S91A;61% 596 S33Y K58Q; K105N; N34S A51G; Y92I; S60K L107N S52Q; P94I; S53RF96Y iPS: 448752 S31N; S57G; T103M; S28Q; A51S; S91A; 59% 544 N32K; S60KK105N; S30A S52Y; Y92I; S33Q L107N S53N S93I; P94Q; F96Y iPS: 448772S31N; S57G; T103M; — A51S; S91A; 59% 594 N32K; S60K K105S; S52Y; Y92I;S33Q Q106G; S53N S93Q; L107D P94N; F96Y iPS: 448117 N32H; S57G; T103M;S28T; Y49F; Y92I; 58% 496 S33V S60K K105S; S30V A51G; S93Q; Q106E; S52Q;P94T; L107D S53R F96Y iPS: 448788 N32R; S57G; T103M; — A51G; S91A; 56%565 S33Q S60K K105Q; S52R; Y92I; Q106G; S53I S93I; L107N P94N; F96Y iPS:448593 S31N; S57G; K105I; — A51S; S91A; 54% 544 N32H; S60K L107D S52Y;Y92I; S33Q S53N S93Q; P94N; F96Y iPS: 448238 N32R; S57G; T103Q; S28R;Y49F; S91A; 53% 527 S33D S60K K105N; S30A A51G; Y92I; Q106E; S53I S93Q;L107D P94N; F96Y iPS: 448901 S31N; S57G; T103R; — A51S; Y92I; 51% 546N32R; S60K K105E; S52Y; S93Q; S33L Q106G; S53N P94Q; L107D; F96Y L110FiPS: 448225 S31N; S57G; K105N; S28M A50V; Y92I; 50% 627 N32R; S60K L107DS53R S93Q; S33L P94N; F96Y iPS: 448730 S31N; S57G; T103V; S28M; A51S;S91A; 50% 525 N32R; S60K K105I; S30A S52Y; Y92I; S33L Q106G; S53N S93I;L107N; P94N; F96Y iPS: 449027 S31N; S57G; T103M; S28Y; A50G; Y92I; 49%521 N32K; S60K K105N; S30V S52R; S93Q; S33Q L107N S53N P94T; F96Y 19H8Wild- — — — — — — 20% 528 Type

The improved affinity variants were produced by recombinant expressionmethods as complete bivalent monoclonal antibodies and/or as monovalentFab-Fc fusions (e.g. Fab region fused to dimeric IgG Fc region) andevaluated for in vitro functional activity in the cell-based cAMP assaydescribed in Example 3. The results of the functional assay are shown inTable 20 below.

TABLE 20 In vitro inhibitory potency of 19H8 variant antibodies andFab-Fc fusion proteins Substitutions with respect Substitutions withrespect PAC1 functional cAMP assay to 19H8 VH sequence to 19H8 VLsequence mAb IC50 Fab-Fc fusion (SEQ ID NO: 296) (SEQ ID NO: 67) in nMprotein HC LC (bivalent IC50 in nM Variant FR1 - HC HC LC FR2 - LCtarget (monovalent Ab ID. CDR1 CDR2 CDR3 CDR1 CDR2 CDR3 binding) targetbinding) iPS: 448202 S31N; S57G; K105N; — Y49F; S91A; 0.32 1.25 N32R;S60K L107D A51G; Y92I; S33L S52Q; S93G; S53R P94M; F96Y iPS: 449375S31N; S57G; K105D; S28Y; S52H; S91A; 0.95 3.48 N32R; S60K L107D S30VS53H Y92I; S33L S93Q; P94E; F96Y iPS: 448083 N32R; S57G; K105E; S28T;Y49F; S91A; — 3.74 S33Q S60K L107D S30V A51G; Y92I; S52Q; S93I; S53RP94N; F96Y iPS: 452128 S31N; S57G; T103M; S28Y; S52N; S91A; 0.38 0.18N32K; S60K K105N; S30V S53M Y92I; S33Q L107N S93N; P94Q; F96Y iPS:448195 S31N; S57G; T103M; S28K; S52N; Y92I; 0.08 0.26 N32K; S60K K105N;S30A; S53M S93Q; S33Q L107N N34V P94Q; F96Y iPS: 448466 S31N; S57G;K105I; — Y49F; S91A; 1.10 1.36 N32K; K58Q; Q106G; A51G; Y92I; S33Q S60KL107D; S52Q; S93Q; L110M S53R P94Q; F96Y iPS: 448689 S31N; S57G; K105N;S28Y; A51S; S91A; 0.20 0.62 N32R; S60K L107D S30V S52Y; Y92I; S33L S53NS93M; P94A; F96Y iPS: 449034 S31N; S57G; K105I; S28P; A51G; S91A; 1.421.58 N32K; S60K L107D S30A; S52R; Y92I; S33Q R31Q S53Y S93Q; P94N; F96YiPS: 448075 S33H S57G; K105D; — Y49F; S91A; 2.10 3.69 S60K L107D A51G;Y92I; S52Q; S93V; S53R P94Q; F96Y iPS: 448924 N32R; S57G; T103M; S28P;Y49F; S91A; 0.45 0.21 S33Y K58Q; K105N; N34S A51G; Y92I; S60K L107NS52Q; P94I; S53R F96Y iPS: 448752 S31N; S57G; T103M; S28Q; A51S; S91A; —0.30 N32K; S60K K105N; S30A S52Y; Y92I; S33Q L107N S53N S93I; P94Q; F96YiPS: 448772 S31N; S57G; T103M; — A51S; S91A; 0.89 2.01 N32K; S60K K105S;S52Y; Y92I; S33Q Q106G; S53N S93Q; L107D P94N; F96Y iPS: 448117 N32H;S57G; T103M; S28T; Y49F; Y92I; 1.26 2.27 S33V S60K K105S; S30V A51G;S93Q; Q106E; S52Q; P94T; L107D S53R F96Y iPS: 448788 N32R; S57G; T103M;— A51G; S91A; 0.09 0.37 S33Q S60K K105Q; S52R; Y92I; Q106G; S53I S93I;L107N P94N; F96Y iPS: 448593 S31N; S57G; K105I; — A51S; S91A; 2.79 20.67N32H; S60K L107D S52Y; Y92I; S33Q S53N S93Q; P94N; F96Y iPS: 448238N32R; S57G; T103Q; S28R; Y49F; S91A; 0.65 1.63 S33D S60K K105N; S30AA51G; Y92I; Q106E; S53I S93Q; L107D P94N; F96Y iPS: 448901 S31N; S57G;T103R; — A51S; Y92I; 0.15 0.41 N32R; S60K K105E; S52Y; S93Q; S33L Q106G;S53N P94Q; L107D; F96Y L110F iPS: 448655 S31N; Y55F; T103M; S28Y; A51S;S91A; — 1.34 N32K; S57R; K105S; S30V S52Y; Y92I; S33Q K58T; Q106E; S53NS93Q; S60K L107D; P94Q; F96Y iPS: 448730 S31N; S57G; T103V; S28M; A51S;S91A; 0.08 0.14 N32R; S60K K105I; S30A S52Y; Y92I; S33L Q106G; S53NS93I; L107N; P94N; F96Y iPS: 449027 S31N; S57G; T103M; S28Y; A50G; Y92I;— 1.85 N32K; S60K K105N; S30V S52R; S93Q; S33Q L107N S53N P94T; F96Y3574 S31N; S57G; T103M; — — — 0.19 — N32K; S60K K105N; S33Q L107N 3575 —— — S28Q; A51S; S91A; 0.14 — S30A S52Y; Y92I; S53N S93I; P94Q; F96Y 19H8Wild- — — — — — —  0.40¹ 8.21 Type ¹Historical value obtained from aprevious assay and included for comparative purposes.

When formatted as Fab-Fc fusion proteins, the 19H8 variants exhibited a2-fold to 58-fold increase in inhibitory potency as compared with theparental 19H8 Fab-Fc fusion protein. Many of the 19H8 variants were morepotent than the 29G4v10 variants when formatted as Fab-Fc fusionproteins (compare results in Table 20 with those in Table 12 for Fab-Fcfusion proteins). When formatted as bivalent monoclonal antibodies, the19H8 variants also exhibited potent human PAC1 neutralizing activitywith IC50 values in the single digit nanomolar or picomolar range.

Example 7. In Vivo Functional Activity of a Human PAC1 Antibody Variantin Cynomolgus Monkeys

To evaluate target engagement in vivo with anti-PAC1 antibody 420653,the ability of the antibody to inhibit maxadilan-induced increase indermal blood flow in cynomolgus monkeys was assessed. Maxadilan is aselective agonist of the PAC1 receptor and can activate the receptor inrodents, cynomolgus monkeys, and humans. As described in Example 4,intradermal administration of maxadilan causes an increase in localdermal blood flow that can be measured by laser Doppler imaging.Inhibition of this effect by anti-PAC1 antibodies can serve as atranslational pharmacodynamic model of antagonism of PAC1 biologicalactivity.

Male cynomolgus monkeys between 5 and 8 years of age were used for thestudy. A dosing solution of maxadilan (Bachem, H6734.0500) was preparedfresh daily by diluting maxadilan stock solution (0.5 mg/mL) in 1×phosphate-buffered saline (PBS). Anti-PAC1 antibody 420653 or 29G4v22,which was tested as a control, were prepared in 10 mM sodium-acetate, 9%sucrose, 0.01% Tween-80, pH 5.2 (A52SuT) at different concentrations,depending on the dose required for the experiment, and administered viaintravenous (i.v.) infusion.

A laser Doppler imager (LDI2-IR, Moor Instruments, Ltd, Wilmington,Del.) was used to measure dermal blood flow (DBF) on a shaved patch ofskin of either the ventral forearm or medial thigh using a low-powerlaser beam generated by a 633 nm helium-neon bulb. The infra-redwavelength was combined with a visible red aiming beam to give a higherweighting to blood flow in the deeper dermis (0.6 to 1 mm). The incidentlight was scattered by static tissue and moving blood. Moving blood inthe microvasculature caused a Doppler light shift. The shifted lightfrom moving blood and the non-shifted light from tissue was thendirected onto 2 square-law detectors. The detected intensityfluctuations were then processed to give parameters of flux(proportional to tissue blood flow) and concentration (proportional tothe concentration of moving blood cells). The measurement resolution was0.2 to 2 mm, with a scanning distance between the instrument apertureand the tissue surface of 20 to 100 cm.

DBF was measured as Flux (relative units) and expressed as % change frombaseline 30 min post-maxadilan administration [100× (individualpost-maxadilan flux-individual baseline flux)/individual baseline flux].Flux units from two separate O-rings were averaged together for eachtest session. The inhibitory effect of the anti-PAC1 antibodies onmaxadilan-induced increase in blood flow (MIIBF) from individual animalswas expressed as % inhibition [100× (Mean of day 0% change frombaseline−individual antibody treated animal % change from baseline)/Meanof day 0% change from baseline].

Following anesthesia and stabilization of vital signs for 15 to 20minutes, rubber O-rings (0.925 cm inner diameter, O-Rings West, Seattle,Wash.) were placed about 0.6 to 1 cm apart from each other on thepre-shaved skin of the ventral forearm or medial thigh without directpositioning over a visible vessel. The limb used for each testingsession was pre-determined, with a different limb used on differenttesting days of the study. After placement of the O-rings on the skin, abaseline measurement was taken. After the baseline scan, a maxadilansolution of 1 ng in 20 μL vehicle (PBS) was injected intradermally atthe center of the O-rings. The O-rings served as a region of interestduring data analysis.

Prior to anti-PAC1 antibody administrations, the time course of MIIBFwas obtained at Day 0. The maxadilan dose of 1 ng was selected based onthe result of a previous maxadilan dose-response in cynomolgus monkeys.After a pre-maxadilan baseline DBF measurement, the time course of DBFresponse to maxadilan intradermal injection was assessed by obtaininglaser Doppler scans at 5, 10, 15, 20, 25, and 30 minutes post-maxadilanapplication. To identify maxadilan responders and eliminatenon-responders from inclusion in the study, a pre-screen procedure priorto antibody administration was implemented. Animals were consideredmaxadilan responders and included in the study if they had a change inDBF flow ≥60 flux units (average of post maxadilan DBF at 30minutes−average of baseline).

Twenty-four cynomolgus monkeys identified as maxadilan respondersreceived either antibody 420653 at a dose of 0.1 mg/kg or 3 mg/kg orantibody 29G4v22 at a dose of 10 mg/kg at Day 0. The antibodies wereadministered via i.v. infusion to the saphenous vein at a rate of 1mL/min by a syringe infusion pump. Post-maxadilan DBF measurements weretaken on Days 2, 4, 7, 10, 14, 21, 28, and 36 using different limbs. Ineach case, DBF was measured by laser Doppler imaging for 30 minutesfollowing 1 ng maxadilan intradermal injection. Whole blood samples forpharmacokinetic (PK) analysis were collected at multiple time pointsincluding prior to antibody dosing, 30 min, 1, 2, 4, 7, 10, 14, 21, 28,35 or 36 and 42 days post-antibody treatment.

As shown in FIG. 10A, antibody 420653 at 3 mg/kg, but not 0.1 mg/kg,significantly prevented MIIBF on Day 2, Day 7, Day 14, and Day 21(post-antibody treatment) compared to Day 0 (pre-antibody treatment)(n=8 animals/group; Bonferroni adjusted p-value=0.0087). Antibody29G4v22 at 10 mg/kg also significantly prevented MIIBF on Day 2 and Day7 (n=8 animals/group)(FIG. 10A). The maximum inhibitory effect ofantibody 420653 at 3 mg/kg was on Day 2 with 96% inhibition, whereas at0.1 mg/kg, antibody 420653 produced a maximum inhibition of 39% on Day 4that was not statistically significant (FIG. 10B). Antibody 29G4v22 at10 mg/kg produced a maximum inhibition of 63% on Day 7 (FIG. 10B).Comparison of antibody 420653 (3 mg/kg) and antibody 29G4v22 (10 mg/kg)at the same time points showed significant differences on Day 2, Day 7,Day 14 and Day 21 (FIG. 10B).

The antibody serum concentrations for antibody 420653 and antibody29G4v22 at days when DBF measurements were taken are shown below inTable 21. The low limit of quantitation (LLOQ) or below quantitationlevel (BQL) was 10 ng/mL for antibody 420653 and 50 ng/mL for antibody29G4v22.

TABLE 21 Serum Concentrations of Antibodies 420653 and 29G4v22 inCynomolgus Monkey Following Antibody Treatment Serum Dose Dose TimePoint Concentration (μg/L) Treatment (mg/kg) (Days) Mean SD n Antibody0.1  2  687 96.6 8 420653  4  315 57.3 8  7  95.9 33.5 8 10* 30.1 10.9 414* LLOQ — 0 Antibody 3  2  36,200 5,010 8 420653  7  14,100 2,170 8 14 5350 2,140 8 21* 2,210 1,800 7 36* 1,480 — 1 Antibody 10  2  113,00028,400 8 29G4v22  7  38,600 8,230 8 14  13,900 6,360 8 21  4,850 2,790 828  1,990 1,490 8 *Fewer PK data points due to some samples withLLOQ/BQL

Overall, these results demonstrate that antibody 420653 significantlyattenuated MIIBF in cynomolgus monkeys when administered at a dose of 3mg/kg. The inhibitory effect of antibody 420653 at 3 mg/kg on MIIBF wasmore robust than antibody 29G4v22 at a higher dose of 10 mg/kg.

All publications, patents, and patent applications discussed and citedherein are hereby incorporated by reference in their entireties. It isunderstood that the disclosed invention is not limited to the particularmethodology, protocols and materials described as these can vary. It isalso understood that the terminology used herein is for the purposes ofdescribing particular embodiments only and is not intended to limit thescope of the appended claims.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

What is claimed:
 1. A method for inhibiting vasodilation in a patient inneed thereof comprising administering to the patient an effective amountof an antibody or antigen-binding fragment thereof that specificallybinds to human pituitary adenylate cyclase-activating polypeptide type 1receptor (PAC1), wherein the antibody or antigen-binding fragmentthereof comprises a light chain variable region comprisingcomplementarity determining regions CDRL1, CDRL2, and CDRL3 and a heavychain variable region comprising complementarity determining regionsCDRH1, CDRH2, and CDRH3, and wherein CDRL1, CDRL2, and CDRL3 have thesequence of SEQ ID NOs: 7, 26, and 36, respectively, and CDRH1, CDRH2,and CDRH3 have the sequence of SEQ ID NOs: 88, 108, and 171,respectively.
 2. The method of claim 1, wherein the light chain variableregion comprises the sequence of SEQ ID NO: 54 and the heavy chainvariable region comprises the sequence of SEQ ID NO:
 194. 3. The methodof claim 1, wherein the antibody or antigen-binding fragment thereof ismonoclonal.
 4. The method of claim 3, wherein the monoclonal antibody orantigen-binding fragment thereof is humanized or fully human.
 5. Themethod of claim 3, wherein the monoclonal antibody comprises a lightchain comprising the sequence of SEQ ID NO: 506 and a heavy chaincomprising the sequence of SEQ ID NO:
 521. 6. The method of claim 1,wherein the patient has a headache condition.
 7. The method of claim 6,wherein the headache condition is migraine or cluster headache.
 8. Amethod for inhibiting activation of human PAC1 in a patient having aheadache condition comprising administering to the patient an effectiveamount of an antibody or antigen-binding fragment thereof thatspecifically binds to human PAC1, wherein the antibody orantigen-binding fragment thereof comprises a light chain variable regioncomprising complementarity determining regions CDRL1, CDRL2, and CDRL3and a heavy chain variable region comprising complementarity determiningregions CDRH1, CDRH2, and CDRH3, and wherein CDRL1, CDRL2, and CDRL3have the sequence of SEQ ID NOs: 7, 26, and 36, respectively, and CDRH1,CDRH2, and CDRH3 have the sequence of SEQ ID NOs: 88, 108, and 171,respectively.
 9. The method of claim 8, wherein the light chain variableregion comprises the sequence of SEQ ID NO: 54 and the heavy chainvariable region comprises the sequence of SEQ ID NO:
 194. 10. The methodof claim 8, wherein the antibody or antigen-binding fragment thereof ismonoclonal.
 11. The method of claim 10, wherein the monoclonal antibodyor antigen-binding fragment thereof is humanized or fully human.
 12. Themethod of claim 10, wherein the monoclonal antibody comprises a lightchain comprising the sequence of SEQ ID NO: 506 and a heavy chaincomprising the sequence of SEQ ID NO:
 521. 13. The method of claim 8,wherein the headache condition is migraine or cluster headache.
 14. Amethod for ameliorating a headache condition in a patient in needthereof comprising administering to the patient an effective amount ofan antibody or antigen-binding fragment thereof that specifically bindsto human PAC 1, wherein the antibody or antigen-binding fragment thereofcomprises a light chain variable region comprising complementaritydetermining regions CDRL1, CDRL2, and CDRL3 and a heavy chain variableregion comprising complementarity determining regions CDRH1, CDRH2, andCDRH3, and wherein CDRL1, CDRL2, and CDRL3 have the sequence of SEQ IDNOs: 7, 26, and 36, respectively, and CDRH1, CDRH2, and CDRH3 have thesequence of SEQ ID NOs: 88, 108, and 171, respectively.
 15. The methodof claim 14, wherein the light chain variable region comprises thesequence of SEQ ID NO: 54 and the heavy chain variable region comprisesthe sequence of SEQ ID NO:
 194. 16. The method of claim 14, wherein theantibody or antigen-binding fragment thereof is monoclonal.
 17. Themethod of claim 16, wherein the monoclonal antibody or antigen-bindingfragment thereof is humanized or fully human.
 18. The method of claim16, wherein the monoclonal antibody comprises a light chain comprisingthe sequence of SEQ ID NO: 506 and a heavy chain comprising the sequenceof SEQ ID NO:
 521. 19. The method of claim 14, wherein the headachecondition is migraine or cluster headache.
 20. The method of claim 19,wherein the migraine is episodic migraine or chronic migraine.
 21. Themethod of claim 14, wherein the antibody or antigen-binding fragmentthereof is administered to the patient diagnosed with the headachecondition as a treatment to reduce reoccurrence of the headachecondition.
 22. The method of claim 14, further comprising administeringto the patient an acute headache therapeutic agent, wherein the acuteheadache therapeutic agent is a triptan, an ergotamine, lasmiditan, anon-steroidal anti-inflammatory, or an opioid.
 23. The method of claim14, further comprising administering to the patient a second headachetherapeutic agent, wherein the second headache therapeutic agent isdivalproex, sodium valproate, valproic acid, topiramate, gabapentin,propranolol, timolol, atenolol, metoprolol, nadolol, amitriptyline,nortriptyline, doxepin, fluoxetine, or onabotulinum toxin A.
 24. Themethod of claim 14, further comprising administering to the patient aCGRP pathway antagonist, wherein the CGRP pathway antagonist iserenumab, galcanezumab, eptinezumab, or fremanezumab.
 25. The method ofclaim 24, wherein the CGRP pathway antagonist is erenumab.
 26. A methodfor ameliorating migraine in a patient diagnosed with migrainecomprising administering to the patient an effective amount of amonoclonal antibody that specifically binds to human PAC1, wherein theantibody comprises a light chain variable region comprisingcomplementarity determining regions CDRL1, CDRL2, and CDRL3 and a heavychain variable region comprising complementarity determining regionsCDRH1, CDRH2, and CDRH3, and wherein CDRL1, CDRL2, and CDRL3 have thesequence of SEQ ID NOs: 7, 26, and 36, respectively, and CDRH1, CDRH2,and CDRH3 have the sequence of SEQ ID NOs: 88, 108, and 171,respectively.
 27. The method of claim 26, wherein the light chainvariable region comprises the sequence of SEQ ID NO: 54 and the heavychain variable region comprises the sequence of SEQ ID NO:
 194. 28. Themethod of claim 26, wherein the monoclonal antibody comprises a lightchain comprising the sequence of SEQ ID NO: 506 and a heavy chaincomprising the sequence of SEQ ID NO:
 521. 29. The method of claim 26,wherein the patient diagnosed with migraine has at least four, but lessthan 15 migraine headache days per month.
 30. The method of claim 26,wherein the patient diagnosed with migraine has 15 or more migraineheadache days per month.
 31. The method of claim 26, wherein themonoclonal antibody is administered to the patient as a treatment toreduce frequency, severity or duration of migraine attacks.
 32. Themethod of claim 26, further comprising administering to the patient aCGRP pathway antagonist, wherein the CGRP pathway antagonist iserenumab, galcanezumab, eptinezumab, or fremanezumab.
 33. The method ofclaim 32, wherein the CGRP pathway antagonist is erenumab.